Nothing Special   »   [go: up one dir, main page]

US9598401B2 - Substituted heteroaryl compounds and methods of use thereof - Google Patents

Substituted heteroaryl compounds and methods of use thereof Download PDF

Info

Publication number
US9598401B2
US9598401B2 US14/787,774 US201414787774A US9598401B2 US 9598401 B2 US9598401 B2 US 9598401B2 US 201414787774 A US201414787774 A US 201414787774A US 9598401 B2 US9598401 B2 US 9598401B2
Authority
US
United States
Prior art keywords
alkyl
alkylene
cycloalkyl
haloalkyl
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/787,774
Other versions
US20160083370A1 (en
Inventor
Yingjun Zhang
Chuanfei JIN
Rongqi ZHOU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunshine Lake Pharma Co Ltd
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Assigned to SUNSHINE LAKE PHARMA CO., LTD. reassignment SUNSHINE LAKE PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JIN, Chuanfei, Zhang, Yingjun, ZHOU, Rongqi
Publication of US20160083370A1 publication Critical patent/US20160083370A1/en
Application granted granted Critical
Publication of US9598401B2 publication Critical patent/US9598401B2/en
Assigned to NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED reassignment NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SUNSHINE LAKE PHARMA CO., LTD.
Assigned to SUNSHINE LAKE PHARMA CO., LTD. reassignment SUNSHINE LAKE PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and more specifically relates to novel compounds, compositions and methods of use thereof for treating central nervous system dysfunction.
  • novel compounds, compositions and methods of use thereof for treating central nervous system dysfunction Particularly, provided herein are substituted heteroaryl compounds acting as 5-serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists.
  • Serotonin a neurotransmitter that carries signal in the brain and nerves, plays a very important role in central nervous system (CNS) dysfunction, especially in anxiety, depression, aggression and impulsivity. Regulation of the central nervous system dysfunction is possible either by antagonistic or agonistic action on a certain type of the serotonin receptors. To date, at least 14 different serotonin receptors have been identified. These receptors can be divided into distinct families—denoted 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 , with subtypes in each family denoted by letters such as a, b and c. Central serotonergic neurons are located in the raphe nuclei in the brain stem.
  • the 5-HT 1A receptor is a G-protein-coupled receptor widely distributed in regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus, and hypothalamus. In these cortico-limbic regions, 5-HT 1A is distributed post-synaptically.
  • the 5-HT 1A receptor also serves as the predominant (somatodendritic) autoreceptor of the raphe nuclei, reducing the firing rate of neurons (the amount of serotonin released per action potential), the synthesis of the neurotransmitter, and thus by implication, the serotonergic activity of its projection areas.
  • Activation of the presynaptic 5-HT 1A , receptor may also indirectly reduce serotonergic transmission through the inhibition of tyrosine hydroxylase synthesis, as well as the activity of glutamatergic pathway that originates in the medial prefrontal cortex and projects to the raphe nuclei (Jonathan Savitz et al., “5-HT 1A receptor function in major depressive disorder,” Prog. Neurobiol., 2009, 88(1): 17-31).
  • Depression is the most important of all therapeutic indications related to 5-HT disorder since it is the fourth leading burdensome disease in the world according to the World Health Organization. By 2020, depression is projected to rank second in disability-adjusted life years (Bromet E et al., “Cross-national epidemiology of DSM-IV major depressive episode,” BMC Med., 2011, 9: 90).
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • the SSRIs boast similar efficacy compared to the TCAs, and an improved AE profile with less tendency for toxicity in overdose (Sarko J, “Andidepressant, old and new. A review of their adverse effects and toxicity in overdose,” Emerg. Med. Clin North Am., 2000, 18 (4): 637-54).
  • SSRIs therapeutically increase available serotonin by inhibiting its reuptake and modulating its transmission.
  • Administration of SSRIs also pleiotropically stimulates pre-synaptic 5-HT 1A autoreceptors, which acutely decreases the release of serotonin and subsequently reduces serotonin concentrations in the synapse.
  • the stimulation of the 5-HT 1A autoreceptors is overcome via desensitization and the SSRIs is able to normalize serotonergic transmission.
  • 5-HT 1A receptor agonists or partial agonists act directly on postsynaptic serotonin receptors to increase serotonin neurotransmission during the SSRI latency effect period.
  • Feiger and Wilcox demonstrated that the buspirone and gepirone were clinically effective 5-HT 1A partial agonists (Feiger, A, Psychopharmacol. Bull., 1996, 32: 659-65).
  • the addition of buspirone to standard SSRI treatment produced a marked improvement in patients previously unresponsive to standard treatment for depression (Dimitriou, E. J., Clin. Psychopharmacol., 1998, 18: 465-9).
  • novel compounds believed to have clinical use in treating CNS disorders through selectively inhibiting serotonin reuptake and/or acting as 5-HT 1A receptor agonists.
  • the compounds disclosed herein are also believed to provide an improvement in potency, pharmacokinetic properties, and/or toxicity profile over certain counterparts found in the art.
  • novel compounds acting as selective serotonin reuptake inhibitors and/or the 5-HT 1A receptor agonists can be used to manufacture medicaments for the treatment of human central nervous system (CNS) dysfunction, such as depression, anxiety disorder and bipolar disorder.
  • CNS central nervous system
  • provided herein are compounds having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X is O, S or NH
  • Y 1 is CH or N
  • Y 2 is CR 2 or N
  • Y 3 is CR 3 or N
  • Y 4 is CR 4 or N
  • E is N or CH
  • G is either a single bond or a double bond, provided that: (1) when is a single bond, G is CH or N; or (2) when is a double bond, G is C;
  • each W is independently O, S or NH;
  • each R x is independently D, F, Cl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NR 11 R 11a , —OR 10 , —(C 1 -C 6 alkylene)-NR 11 R 11a , (C 1 -C 6 alkylene)-OR 10 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a or —(C 1 -C 6 alkylene)-aryl, or two R x on two adjacent ring carbon atoms, together with the ring carbon atoms to which they are attached, form a C 3 -C 6 carbocyclic or 3-6 membered heterocyclic ring;
  • k 0, 1, 2, 3 or 4;
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, Br, I, NO 2 , CN, —SCN, —OR 10 , —SR 10 , —NR 11 R 11a , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )C( ⁇ O)R 10 , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, aryl
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, Br, I, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , -alkylene-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene
  • each R 8 is independently H, D, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, wherein each of alkenyl, alkynyl, alkoxy and cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each R 9 is independently D, F, Cl, Br, I, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of
  • each R 10 is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio and alkylamino;
  • each R 11 and R 11a is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene and heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio and alky
  • n 3, 4, 5 or 6.
  • the compounds disclosed herein have Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, NO 2 , CN, —OR 10 , —SR 10 , —NR 11 R 11a , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )C( ⁇ O)R 10 , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, (C 3 -C 10 cycl
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, NO 2 , CN, —OR 10 , —SR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)-(C 1 -C 4 alkylene)-, C 2 -C 7 heterocyclyl, (C 2 -C 7 heterocyclyl)-(C 1 -C 4 alkylene)-, phenyl, (phenyl)-(C 1 -C 4 alkylene)-, C 1 -C 5 heteroaryl or (C 1 -C 5 heteroaryl)-(C 1 -C 4 alkylene)-, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 6 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 4 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, with the pro
  • each R 8 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 3 -C 10 cycloalkyl, wherein each of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy and C 3 -C 10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 3 -C 10 cycloalkyl, C 2 -C 10 heterocyclyl, C 6 -C 10 aryl and C 1 -C 9 heteroaryl.
  • each R 8 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 3 -C 8 cycloalkyl, wherein each of C 1 -C 4 alkoxy and C 3 -C 8 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino.
  • each R 9 is independently D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 3 -C 10 cycloalkyl, (C
  • each R 9 is independently D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -
  • each R 10 is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 10 cycloalkyl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylamino; and
  • each R 11 and R 11a is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 10 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 10 heterocyclic ring, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl and C 2 -C 10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylamino.
  • each R x is independently D, Cl, Me, —CF 3 , —OMe, OH or NH 2 ;
  • k 0, 1, 2, 3 or 4;
  • R 1 is H, D, F, Cl, CN, —OR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl or C 1 -C 5 heteroaryl, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl and C 1 -C 5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino;
  • each of R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 4 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, with the proviso that at least one of R 5 , R 6 and R 7 is not H, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino is optionally substituted with one or
  • each R 10 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl;
  • each R 11 and R 11a is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 7 heterocyclic ring; and
  • n 3, 4, 5 or 6.
  • R 1 is H, D, F, Cl, CN, OH, NH 2 , Me, Et, n-Pr, i-Pr, —CF 3 , —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe 2 .
  • each of R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OMe, —C( ⁇ O)NH 2 , —CH 2 —C( ⁇ O)NH 2 , —C( ⁇ O)NMe 2 , Me, Et, n-Pr, i-Pr, —CF 3 , —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe 2 , with the proviso that at least one of R 5 , R 6 and R 7 is not H.
  • R 1 is H, D, F, Cl, CN, —OR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl or C 1 -C 5 heteroaryl, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl and C 1 -C 5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino;
  • R 8 is H, D, C 1 -C 4 alkyl or C 1 -C 4 alkoxy
  • R 9 is D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio
  • each R 10 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl;
  • each R 11 and R 11a is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 7 heterocyclic ring; and
  • n 3, 4, 5 or 6.
  • R 1 is H, D, F, Cl, CN, OH, NH 2 , Me, —CF 3 , —OMe or —NMe 2 .
  • R 8 is H, D, Me, Et, i-Pr, t-Bu or —OMe.
  • R 9 is D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OMe, —C( ⁇ O)OEt, —C( ⁇ O)NH 2 , —C( ⁇ O)NMe 2 , Me, Et, —CF 3 or —OMe.
  • composition containing the compound disclosed herein.
  • the pharmaceutical composition disclosed herein further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof.
  • the pharmaceutical composition disclosed herein further comprises at least one therapeutic agent for central nervous system dysfunction, wherein the therapeutic agent for central nervous system dysfunction is an antidepressant, an antianxiety agent, a lithium agent of mood stabilizer, an atypical antipsychotic agent, an antiepileptic agent, an anti-Parkinson agent, a selective serotonin reuptake inhibitor, a 5-HT 1A receptor agonist, a central nervous system stimulant, a nicotine antagonist or a combination thereof.
  • the therapeutic agent for central nervous system dysfunction is an antidepressant, an antianxiety agent, a lithium agent of mood stabilizer, an atypical antipsychotic agent, an antiepileptic agent, an anti-Parkinson agent, a selective serotonin reuptake inhibitor, a 5-HT 1A receptor agonist, a central nervous system stimulant, a nicotine antagonist or a combination thereof.
  • the therapeutic agent is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, s
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal, including a human being.
  • provided herein is a method of preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the mammal, including a human being.
  • provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal, including a human being.
  • the central nervous system dysfunction is depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom or premenstrual tension syndrome.
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for selectively inhibiting serotonin reuptake.
  • provided herein is a method of selectively inhibiting serotonin reuptake with the compound or the pharmaceutical composition disclosed herein.
  • provided herein is the compound or the pharmaceutical composition disclosed herein for use in selectively inhibiting serotonin reuptake.
  • any embodiment disclosed herein can be combined with other embodiments as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention.
  • any technical feature in one embodiment can be applied to the corresponding technical feature in other embodiment as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention.
  • grammatical articles “one”, “a”, “an” and “the”, as used herein, are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses and species of the invention.
  • substituted refers to the replacement of one or more hydrogen groups in a given structure with the group of a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • substituents include D, F, Cl, N 3 , —CN, —OH, —SH, —NH 2 , alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
  • unsaturated refers to a moiety having one or more units of unsaturation.
  • substituents of the compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual subcombination of the members of such groups and ranges.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • halogen or “halo”, which may be used interchangeably herein, refers to F, Cl, Br or I.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms. In another embodiment, the alkyl group contains 1-6 carbon atoms. In still another embodiment, the alkyl group contains 1-4 carbon atoms. In yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group is optionally substituted with one or more substituents described herein.
  • alkyl group examples include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), n-propyl (n-Pr, —CH 2 CH 2 CH 3 ), isopropyl (i-Pr, —CH(CH 3 ) 2 ), n-butyl (n-Bu, —CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, —CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, —CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, —C(CH 3 ) 3 ), n-pentyl (—CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (—CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (—C(CH 3 ) 2 CH
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms. In another embodiment, the alkylene group contains 1-4 carbon atoms. In still another embodiment, the alkylene group contains 1-3 carbon atoms. In yet another embodiment, the alkylene group contains 1-2 carbon atoms.
  • the alkylene group is exemplified by methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), isopropylene (—CH(CH 3 )CH 2 —), and the like. The alkylene group is optionally substituted with one or more substituents described herein.
  • alkenyl refers to a linear or branched chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, and includes groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • the alkenyl group contains 2-8 carbon atoms.
  • the alkenyl group contains 2-6 carbon atoms.
  • the alkenyl group contains 2-4 carbon atoms.
  • alkenyl group examples include ethenyl or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), and the like.
  • the alkenyl group is optionally substituted with one or more substituents described herein.
  • alkynyl refers to a linear or branched-chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl group is optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms.
  • the alkynyl group contains 2-6 carbon atoms.
  • the alkynyl group contains 2-4 carbon atoms.
  • alkynyl group examples include ethynyl (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), 1-propynyl (—C ⁇ C—CH 3 ), and the like.
  • the alkynyl group is optionally substituted with one or more substituents described herein.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom, wherein the alkyl group is as defined herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In still another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
  • alkoxy group examples include methoxy (MeO, —OCH 3 ), ethoxy (EtO, —OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, —OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, —OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, —OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, —OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, —OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, —OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (—OCH(CH 3 ) 3 ), 1-
  • haloalkyl or “haloalkoxy” refers to an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and alkoxy group are as defined herein.
  • Some non-limiting examples of the haloalkyl group and the haloalkoxy group include chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like.
  • the haloalkyl group or the haloalkoxy group is optionally substituted with one or more substituents described herein.
  • alkylamino embraces “N-alkylamino” and “N,N-dialkylamino”, wherein the amino group is independently substituted with one or two alkyl groups, respectively.
  • the alkylamino group is lower alkylamino group having one or two alkyl groups of 1 to 6 carbon atoms, which are attached to a nitrogen atom.
  • the alkylamino group is lower alkylamino group having 1 to 4 carbon atoms.
  • alkylamino group examples include monoalkylamino or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.
  • the alkylamino group is optionally substituted with one or more substituents described herein.
  • alkylthio refers to a group containing a linear or branched alkyl group of 1 to 10 carbon atoms attached to a divalent sulfur atom.
  • the alkylthio group is lower alkylthio group having 1 to 4 carbon atoms.
  • Some non-limiting examples of the alkylthio group include methylthio (CH 3 S—).
  • the alkylthio group is optionally substituted with one or more substituents described herein.
  • cycloalkyl refers to a saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system, wherein the bicyclic or tricyclic ring system may include fused ring, bridged ring and spiro ring.
  • the cycloalkyl group contains 3-10 carbon atoms.
  • the cycloalkyl group contains 3-8 carbon atoms.
  • the cycloalkyl group contains 3-6 carbon atoms.
  • the cycloalkyl group is optionally substituted with one or more substituents described herein.
  • cycloalkylalkylene refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and cycloalkyl group are as defined herein.
  • the cycloalkylalkylene group is lower cycloalkylalkylene group in which the cycloalkyl group is attached to an alkyl group having 1 to 6 carbon atoms.
  • the cycloalkyl group is attached to an alkyl group having 1 to 4 carbon atoms.
  • the cycloalkyl group is attached to an alkyl group having 1 to 3 carbon atoms.
  • the cycloalkylalkylene group is optionally substituted with one or more substituents described herein.
  • heteroatom refers to one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including any oxidized form of nitrogen (N), sulfur (S) or phosphorus (P); the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
  • heterocycle refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom as defined herein and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the rest of the molecule.
  • the “heterocycle”, “heterocyclyl” or “heterocyclic” group is a monocycle having 3 to 8 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , or PO or PO 2 , with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 12 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO 2 , or PO or PO 2 ).
  • the “heterocycle”, “heterocyclyl” or “heterocyclic” group is optionally substituted with one or more substituents described herein.
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • Some non-limiting examples of the heterocyclyl group include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl
  • heterocyclylalkylene refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the alkyl group and heterocyclyl group are as defined herein.
  • the heterocyclylalkylene group is lower heterocyclylalkylene group in which the heterocyclyl group is attached to an alkyl group having 1 to 6 carbon atoms.
  • the heterocyclyl group is attached to an alkyl group having 1 to 4 carbon atoms.
  • Some non-limiting examples of the heterocyclylalkylene group include 2-pyrrolidinoethyl, and the like.
  • the heterocyclylalkylene group is optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, preferably, 6 to 10 ring members, and more preferably 6 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members.
  • the aryl group is generally, but not necessarily bonded to the parent molecule through an aromatic ring of the aryl group.
  • aryl may be used interchangeably with the term “aryl ring” or “aromatic ring”.
  • Some non-limiting examples of the aryl group include phenyl, naphthyl and anthracene.
  • the aryl group is optionally substituted with one or more substituents described herein.
  • arylalkylene refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein.
  • the arylalkylene group is lower arylalkylene group in which the aryl group is attached to an alkyl group having 1 to 6 carbon atoms.
  • the arylalkylene group is “phenylalkylene” containing alkyl groups of 1 to 4 carbon atoms.
  • Some non-limiting examples of the arylalkylene group include benzyl, diphenylmethyl, phenylethyl, and the like.
  • the arylalkylene group is optionally substituted with one or more substituents described herein.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 5 to 7 ring members.
  • the heteroaryl group is generally, but not necessarily bonded to the parent molecule through an aromatic ring of the heteroaryl group.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic ring”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl group include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thi
  • heteroarylalkylene refers to an alkyl group substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl group are as defined herein.
  • the heteroarylalkylene group is lower heteroarylalkylene groups in which the heteroaryl group is attached to an alkyl group having 1 to 6 carbon atoms.
  • the heteroaryl group is attached to an alkyl group having 1 to 4 carbon atoms.
  • Some non-limiting examples of the heteroarylalkylene group include 2-pyridylmethyl, 3-furylethyl, and the like.
  • the heteroarylalkylene group is optionally substituted with one or more substituents described herein.
  • carbonyl refers to —(C ⁇ O)—.
  • acyl refers to —(C ⁇ O)—R.
  • carbamoyl refers to —C( ⁇ O)NH 2 .
  • azido refers to —N 3 .
  • the azido group can be attached to other groups, for example, to methyl to form methylazide (MeN 3 ), or to phenyl to form phenylazide (PhN 3 ).
  • a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the rings to which it is attached.
  • Figure a represents possible substitution in any of the position on the ring B.
  • spirocyclyl refers to a ring system wherein a ring originating from a particular annular carbon of another ring.
  • ring A and ring B share a carbon atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl”.
  • Each ring in the spiro bicyclyl can be either a carbocyclyl or a heterocyclyl.
  • spiro bicyclyl group examples include 4-oxaspiro[2.4]hept-6-yl, and (R)-4-azaspiro[2.4]hept-6-yl.
  • the spiro bicyclyl group is optionally substituted with one or more substituents described herein.
  • fused bicyclic ring refers to a bridged ring system in which two rings share a common C—C bond.
  • two five-membered rings Figure e
  • two six-membered rings Figure f
  • a five-membered ring and a six-membered ring Figure g
  • Such a ring system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon).
  • Each ring in the fused bicyclic ring system is independently carbocyclic ring or heterocyclic ring.
  • fused bicyclyl group examples include hexahydrofuro[2,3-b]furan-3-yl, hexahydrofuro[3,2-b]furan-3-yl, octahydrocyclopenta[c]pyrrol-5-yl, octahydropentalen-2-yl, octahydro-1H-isoindol-5-yl, and the like.
  • the fused bicyclyl group is optionally substituted with one or more substituents described herein.
  • stereoisomer refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
  • diastereoisomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • enantiomer refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • racemate or “racemic mixture” refers to an equimolar mixture of two enantiomeric species devoid of optical activity.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and l or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response or other problem or complication commensurate with a reasonable benefit/risk ratio, and effective for their intended purpose.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I). Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation of the prodrug form in blood or tissue to the parent form.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound.
  • phosphates such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Pro - drugs as Novel Delivery Systems , Vol. 14, A.C.S. Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al, Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by a process comprising contacting a compound disclosed herein with a mammal for a sufficient time period.
  • pharmaceutically acceptable salt refers to a salt which is, within the scope of sound medical judgement, suitable for contacting tissues of human and lower animals without showing excessive toxicity, irritation and anaphylactic response, and is commensurate to reasonable effect/risk ratio.
  • the pharmaceutically acceptable salt is well known in the art. For example, S. M. Berge, et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1.
  • Some non-limiting examples of pharmaceutically acceptable salts derived from nontoxic acids include acetate, adipate, alginate, citrate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, maleate, laurate, laurylsulfate, malate, malonate, methanesulfonate, nicotinate, 2-napsylate, oxalate, nitrate,
  • compositions derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -C 8 sulfonate and aryl sulfonate.
  • counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -C 8 sulfonate and aryl sulfonate.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvents that form the solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate can be used when said solvent is water.
  • one solvent molecule is associated with one molecule of the compounds disclosed herein, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a dihydrate.
  • less than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a hemihydrate.
  • all the solvates of the invention retain the biological effectiveness of the non-hydrate form of the compounds disclosed herein.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • suitable amino-protecting groups include acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethylenoxycarbonyl (Fmoc) and benzyl.
  • hydroxy-protecting group refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • suitable hydroxy-protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Examples of common carboxy-protecting groups include —CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like.
  • protecting groups and their use see Greene et al., Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups , Thieme, Stuttgart, 2005.
  • preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • terapéuticaally effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the condition, age, weight, gender etc. of the subject to be treated.
  • Treating” or “treatment” of a disease state includes: (i) preventing the disease state, i.e., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, (ii) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or (iii) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • heteroaryl compounds Disclosed herein are heteroaryl compounds, pharmaceutically acceptable salts thereof, pharmaceutical formulations thereof and compositions thereof, which are acting as selective serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists and have potential therapeutic uses for the treatment of human central nervous system (CNS) dysfunction, such as depression, anxiety disorder or bipolar disorder.
  • CNS central nervous system
  • provided herein are compounds having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • X is O, S or NH
  • Y 1 is CH or N
  • Y 2 is CR 2 or N
  • Y 3 is CR 3 or N
  • Y 4 is CR 4 or N
  • E is N or CH
  • G is either a single bond or a double bond, provided that: (1) when is a single bond, G is CH or N; or (2) when is a double bond, G is C;
  • each W is independently O, S or NH;
  • each R x is independently D, F, Cl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NR 11 R 11a , —OR 10 , —(C 1 -C 6 alkylene)-NR 11 R 11a , —(C 1 -C 6 alkylene)-OR 10 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a or —(C 1 -C 6 alkylene)-aryl, or two R x on two adjacent ring carbon atoms, together with the ring carbon atoms to which they are attached, form a C 3 -C 6 carbocyclic or 3-6 membered heterocyclic ring;
  • k 0, 1, 2, 3 or 4;
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, Br, I, NO 2 , CN, —SCN, —OR 10 , —SR 10 , —NR 11 R 11a , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )C( ⁇ O)R 10 , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, aryl
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, Br, I, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , -alkylene-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene
  • each R 8 is independently H, D, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, wherein each of alkenyl, alkynyl, alkoxy and cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each R 9 is independently D, F, Cl, Br, I, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of
  • each R 10 is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio and alkylamino;
  • each R 11 and R 11a is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene and heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , alkyl, alkoxy, alkylthio and alky
  • n 3, 4, 5 or 6.
  • the compounds disclosed herein have Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, NO 2 , CN, —OR 10 , —SR 10 , —NR 11 R 11a , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )C( ⁇ O)R 10 , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, (C 3 -C 10 cycl
  • each of R 1 , R 2 , R 3 and R 4 is independently H, D, F, Cl, NO 2 , CN, —OR 10 , —SR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)-(C 1 -C 4 alkylene)-, C 2 -C 7 heterocyclyl, (C 2 -C 7 heterocyclyl)-(C 1 -C 4 alkylene)-, phenyl, (phenyl)-(C 1 -C 4 alkylene)-, C 1 -C 5 heteroaryl or (C 1 -C 5 heteroaryl)-(C 1 -C 4 alkylene)-, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 6 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -
  • each R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 4 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, with the pro
  • each R 8 is independently H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 3 -C 10 cycloalkyl, wherein each of C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy and C 3 -C 10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 3 -C 10 cycloalkyl, C 2 -C 10 heterocyclyl, C 6 -C 10 aryl and C 1 -C 9 heteroaryl.
  • each R 8 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 3 -C 8 cycloalkyl, wherein each of C 1 -C 4 alkoxy and C 3 -C 8 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino.
  • each R 9 is independently D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 3 -C 10 cycloalkyl, (C
  • each R 9 is independently D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , —N(R 11 )C( ⁇ O)R 10 , —S( ⁇ O)R 10 , —S( ⁇ O) 2 R 10 , —S( ⁇ O) 2 OR 10 , —S( ⁇ O) 2 NR 11 R 11a , —N(R 11 )S( ⁇ O) 2 R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -
  • each R 10 is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 10 cycloalkyl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylamino; and
  • each R 11 and R 11a is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 10 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 10 heterocyclic ring, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl and C 2 -C 10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylamino.
  • each R x is independently D, Cl, Me, —CF 3 , —OMe, OH or NH 2 ;
  • k 0, 1, 2, 3 or 4;
  • R 1 is H, D, F, Cl, CN, —OR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl or C 1 -C 5 heteroaryl, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl and C 1 -C 5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino;
  • each of R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —(C 1 -C 4 alkylene)-C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, with the proviso that at least one of R 5 , R 6 and R 7 is not H, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino is optionally substituted with one or
  • each R 10 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl;
  • each R 11 and R 11a is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 7 heterocyclic ring; and
  • n 3, 4, 5 or 6.
  • R 1 is H, D, F, Cl, CN, OH, NH 2 , Me, Et, n-Pr, i-Pr, —CF 3 , —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe 2 .
  • each of R 5 , R 6 and R 7 is independently H, D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OMe, —C( ⁇ O)NH 2 , —CH 2 —C( ⁇ O)NH 2 , —C( ⁇ O)NMe 2 , Me, Et, n-Pr, i-Pr, —CF 3 , —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe 2 , with the proviso that at least one of R 5 , R 6 and R 7 is not H.
  • R 1 is H, D, F, Cl, CN, —OR 10 , —NR 11 R 11a , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl or C 1 -C 5 heteroaryl, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 7 heterocyclyl, phenyl and C 1 -C 5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino;
  • R 8 is H, D, C 1 -C 4 alkyl or C 1 -C 4 alkoxy
  • R 9 is D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)R 10 , —C( ⁇ O)OR 10 , —C( ⁇ O)NR 11 R 11a , —OC( ⁇ O)R 10 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino, wherein each of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N 3 , CN, OH, SH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio
  • each R 10 is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl;
  • each R 11 and R 11a is independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 8 cycloalkyl, or R 11 and R 11a , together with the nitrogen atom to which they are attached, form a C 2 -C 7 heterocyclic ring; and
  • n 3, 4, 5 or 6.
  • R 1 is H, D, F, Cl, CN, OH, NH 2 , Me, —CF 3 , —OMe or —NMe 2 .
  • R 8 is H, D, Me, Et, i-Pr, t-Bu or —OMe.
  • R 9 is D, F, Cl, NO 2 , CN, NH 2 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OMe, —C( ⁇ O)OEt, —C( ⁇ O)NH 2 , —C( ⁇ O)NMe 2 , Me, Et, —CF 3 or —OMe.
  • the compounds disclosed herein have one of the following structures:
  • the invention includes all suitable isotopic variations of the compounds disclosed herein.
  • An isotopic variation of the compounds disclosed herein is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature with the most abundant isotope(s) being preferred.
  • isotopes that can be incorporated into the compounds disclosed herein include the isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine, such as H 2 , H 3 , C 11 , C 13 , C 14 , N 15 , O 17 , O 18 , S 35 , F 18 and Cl 36 , respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., H 3 , and carbon-14, i.e., C 14 , isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., H 2 , may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds disclosed herein can generally be prepared by conventional procedures such as using appropriate isotopic variations of suitable reagents.
  • Also part of the invention are those compounds wherein at least one atom has been replaced by an isotope of a different atom that can be used in vivo imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography (PET).
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • Examples for such derivatives usable in SPECT studies are compounds wherein a Tc 99m , In 111 , Rb 82 , Cs 137 , I 123 , Ga 67 , Ir 192 or Tl 201 and preferably I 123 has been introduced (for iodination see e.g.: Coenen et al., Radioiodination Reactions for Pharmaceuticals, Compendium for Effective Synthesis Strategies , Springer, Dordrecht, 2006), while for PET applications C 11 , N 13 , O 15 , F 18 , Rb 82 , Sr 82 , and preferably F 18 (Coenen et al., Fluorine -18 labeling methods: Features and possibilities of basic reactions , Ernst Schering Res Found Workshop, 2007, Vol 62, p 15-50; Miller et al., Ang Chem Int Ed, 2008, Vol 47, p 8998) may be used.
  • structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the compounds disclosed herein are within the scope of the invention.
  • stereoisomeric e.g., enantiomeric, diastereomeric, and geometric (or conformational)
  • N-oxides of the compounds disclosed herein are also within the scope of the invention and may be prepared by oxidation of the corresponding nitrogen base using a conventional oxidizing agent such as hydrogen peroxide in the presence of an acid such as acetic acid at an elevated temperature, or by reaction with a peracid such as peracetic acid in a suitable solvent, e.g. dichloromethane, ethyl acetate or methyl acetate, or in chloroform or dichloromethane with 3-chloroperoxybenzoic acid.
  • a conventional oxidizing agent such as hydrogen peroxide in the presence of an acid such as acetic acid at an elevated temperature
  • a peracid such as peracetic acid in a suitable solvent, e.g. dichloromethane, ethyl acetate or methyl acetate, or in chloroform or dichloromethane with 3-chloroperoxybenzoic acid.
  • salts of the compounds disclosed herein include pharmaceutically acceptable salts thereof, as well as other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I), (II), (III), (IV) or (V) and/or for separating enantiomers of compounds of Formula (I), (II), (III), (IV) or (V).
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha-hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.
  • an inorganic acid such as hydrochloric acid, hydro
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
  • an pharmaceutical composition comprising the compound of Formula (I), (II), (III), (IV) or (V), or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, in admixture with at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.
  • Appropriate carriers, adjuvants and vehicles are well known to those of skill in the art and described in, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 2004, Lippincott, Williams & Wilkins, Philadelphia; Gennaro et al., Remington: The Science and Practice of Pharmacy, 2000, Lippincott, Williams & Wilkins, Philadelphia; and Rowe et al., Handbook of Pharmaceutical Excipients, 2005, Pharmaceutical Press, Chicago.
  • the compounds or compositions disclosed herein may be administered by any suitable means, including oral (including buccal and sublingual), topical, rectal, vaginal, transdermal, parenteral (intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous), intrapulmonary, intradermal, intrathecal, epidural and intranasal, as well as intralesional administration if desired for local treatment.
  • oral including buccal and sublingual
  • topical including buccal and sublingual
  • vaginal vaginal
  • transdermal transdermal
  • parenteral intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous
  • intrapulmonary intradermal
  • intrathecal epidural and intranasal
  • intralesional administration if desired for local treatment.
  • the preferred method is oral administration, intraperitoneal or intravenous administration.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol) and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solvent, dispersant, suspending agent or emulsifying agent, as well as sterile dispersant for reforming a sterile injectable solution or dispersion.
  • suitable aqueous or nonaqueous carriers, diluents, solvents or media include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oil (such olive oil), injectable organic esters such as ethyl oleate and suitable mixtures thereof.
  • compositions can further comprise excipients, such as preservative, wetting agent, emulsifying agent and dispersant.
  • excipients such as preservative, wetting agent, emulsifying agent and dispersant.
  • excipients such as preservative, wetting agent, emulsifying agent and dispersant.
  • various antibacterial agents and antifungal agents such as nipagins, nautisan, phenol, sorbic acid, etc. can ensure effects of combating microorganisms.
  • isotonizing agents such as sugars, sodium chloride, etc.
  • substances for absorption delay such as aluminum monostearate and gelatin, can achieve the prolonged absorption of injectable dosage form.
  • the suspensions can further comprise a suspending agent, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan, microcrystalline cellulose, meta-aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.
  • a suspending agent such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan, microcrystalline cellulose, meta-aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.
  • the absorption rate of subcutaneously or intramuscularly administered drug for prolonging the effect of drug.
  • This may be reached by using a liquid suspension of crystal or amorphous form with poor water solubility.
  • the absorption rate of drug depends on its dissolution rate, while the dissolution rate depends on the size and form of crystal.
  • the delayed absorption of drug in parenteral administration may be reached by dissolving or dispersing the drug in an oil medium.
  • An injectable depot dosage form may be prepared by forming microcapsule substrate of drug in a biodegradable polymer such as polylactide-polyglycolide.
  • the release rate of drug may be controlled according to the ratio of drug to polymer and the properties of the specifically used polymer.
  • biodegradable polymer comprise poly (orthoesters) and poly (anhydrides).
  • the injectable depot dosage form can also be prepared by embedding drug in a liposome or microemulsion compatible to body tissues.
  • the injectable preparation may be sterilized by filtration using a bacterial filter or by incorporating a sterilizing agent in the form of a sterile solid composition, and the solid composition may be dissolved or dispersed in sterile water or other sterile injectable media before clinical application.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia
  • mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention
  • compositions disclosed herein can be in the form of a rectal or vaginal suppository. These can be prepared by mixing the agent with the appropriate non-perfusion adjuvant. The mixture prepared this way is a solid at room temperature, but it becomes a liquid at rectal or vaginal temperature and releases the drug in the rectum or vagina.
  • Such substances include cocoa fat, beeswax and polyethylene glycol.
  • the active compounds disclosed herein are conveniently delivered in the form of an aerosol spray from a pressurized container or a nebulizer or from a capsule using an inhaler or insufflators.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the medicament for pressurized container or nebulizer may contain a solution or suspension of the active compound, while for a capsule, it preferably should be in the form of powder.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound disclosed herein and a suitable powder base (e.g., lactose or starch).
  • a powder mix of a compound disclosed herein and a suitable powder base (e.g., lactose or starch).
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or “puff” of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound disclosed herein.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total amount per day of the compound or composition disclosed herein must be determined by a physician within the range of reliable medical decisions.
  • the specific therapeutically amount must be determined based on various factors, including the diseases to be treated and severity thereof; the activity of the used specific compound; the used specific composition; the age, body weight, general health status, gender and food of patient; the administration time, route and excretory rate of the used specific compound; the duration of the treatment; the drug administered in combination or simultaneously with the specific compound; and similar factors well known in the art of medicine.
  • the dose of a compound of Formula (I), (II), (III), (IV) or (V) for mammals especially human may be 0.1-1000 mg/kg body weight per day, preferably 1-100 mg/kg body weight per day.
  • the administration may be once or several times a day, and each administration may include 1, 2 or 3 doses.
  • the compound of Formula (I), (II), (III), (IV) or (V) may either be administered alone or in combination with another therapeutically active compound, wherein the two compounds may either be administered simultaneously or sequentially.
  • Some non-limiting examples of the therapeutically active compound which may advantageously be combined with the compounds of Formula (I), (II), (III), (IV) or (V) include sedatives or hypnotics, such as benzodiazepines; anticonvulsants, such as lamotrigine, valproic acid, topiramate, gabapentin, and carbamazepine; mood stabilizers such as lithium; dopaminergic drugs, such as dopamine agonists and L-Dopa; drugs to treat ADHD, such as atomoxetine; psychostimulants, such as modafinil, ketamine, methylphenidate and amphetamine; other antidepressants, such as mirtazapine, mianserin and buproprion; hormones, such as T3, estrogen, DHE
  • the compounds and pharmaceutical compositions disclosed herein can be used in the manufacture of a medicament for preventing, treating or lessening the severity of a central nervous system dysfunction in mammals including humans, as well as for inhibiting serotonin reuptake and/or acting as 5-HT 1A receptor agonists.
  • amount of the compounds used in the compositions disclosed herein is efficient to inhibit serotonin reuptake detectably and selectively, and has agonistic action for 5-HT 1A receptor.
  • the compounds disclosed herein may be the agents used for treatment of the human central nervous system (CNS) dysfunction such as depression, anxiety.
  • the compounds disclosed herein may be used for, but not limited to, preventing, treating or lessening the severity of central nervous system dysfunction in mammals including humans by administering an effective amount of the compounds or compositions disclosed herein to patient.
  • Such human central nervous system dysfunctions responsed to 5-HT receptor further include, but are not limited to, depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom or premenstrual tension syndrome.
  • these compounds and compositions are also useful for veterinary treatment of companion animals, exotic animals and mammals of farm animals.
  • animals include horses, dogs and cats.
  • the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I), except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous THF, dioxane, toluene and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4 prior to use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were generally determined on Agilent 1200 or Agilent 6120 Series LC-MS (Column Type: Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 micron, 6 min, and 0.6 mL/min flow rate).
  • the mobile phase was 5-95% (0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 O), and the generated chromatograms were monitored at 210/254 nm by UV detector with low response EFI mode (ESI).
  • each R 1 , R 5 , R 6 , R 7 , R 8 and R 9 has the definitions as described herein.
  • Compound (8) can be prepared by the process illustrated in Scheme 1. Firstly, 6-hexanolactone (1) can be converted to compound (2) by alcoholysis with sulfuric acid as a catalyst and then oxidation in the presence of PCC. Then compound (2) can react with compound (3) to form compound (4) by Fischer indole cyclization in an alcoholic solvent such as ethanol, isopropanol or tert-butanol. Compound (4) can further react with a reducing agent such as lithium aluminum hydride to form compound (5) at a suitable temperature such as 40-120° C.
  • a reducing agent such as lithium aluminum hydride
  • the hydroxyl group of compound (5) can be converted to p-toluenesulfonate group to form compound (6), and then compound (6) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (8) by nucleophilic substitution.
  • an inorganic base such as potassium carbonate or sodium carbonate
  • an organic base such as triethylamine
  • a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF
  • Compound (8) can also be prepared by the process illustrated in Scheme 2. Firstly, Friedel-Crafts acylation reaction of compound (9) with chlorobutyryl chloride can give compound (10). Compound (10) can then react with a reducing agent such as sodium borohydride or lithium aluminum hydride to afford compound (11) in a suitable solvent such as tert-butanol or isopropanol.
  • a reducing agent such as sodium borohydride or lithium aluminum hydride
  • compound (11) can be converted to p-toluenesulfonate group to form compound (6), and compound (6) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (8) by nucleophilic substitution.
  • an inorganic base such as potassium carbonate or sodium carbonate
  • organic base such as triethylamine
  • a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF
  • Compound (16) can be prepared by the process illustrated in Scheme 3. Firstly, tetrahydropyrane (13) can react with compound (3) to give compound (14) by Fischer indole cyclization at a suitable temperature such as 40-120° C. Then the hydroxyl group of compound (14) can be converted to p-toluenesulfonate group to form compound (15), and compound (15) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (16) by nucleophilic substitution.
  • an inorganic base such as potassium carbonate or sodium carbonate
  • an organic base such as triethylamine
  • Compound (19) can be prepared by the process illustrated in Scheme 4. Firstly, compound (17) can be converted to compound (18) by reacting with anhydrous piperazine. Then nucleophilic substitution reaction of compound (18) with compound (6) can give the objective compound (19) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO and at a suitable temperature such as 30-100° C.
  • an inorganic base such as potassium carbonate or sodium carbonate
  • an organic base such as triethylamine
  • a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO
  • Compound (20) can be prepared by the process illustrated in Scheme 5. Nucleophilic substitution reaction of compound (17) with compound (15) can give the objective compound (20) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO and at a suitable temperature such as 30-100° C.
  • an inorganic base such as potassium carbonate or sodium carbonate
  • an organic base such as triethylamine
  • a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 262.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 220.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 374.1 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (216 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (148 mg, 60.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 266.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 224.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 378.1 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22 g, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (0.13 g, 0.58 mmol), potassium carbonate (0.12 g, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (160 mg, 64%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 250.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 208.2 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 362.2 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (168 mg, 70%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 369.2 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (163 mg, 67.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 330.2 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (191 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (155 mg, 70%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 206.0 [M+H] + .
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 360.1 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (208 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (167 mg, 70.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 364.1 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21 g, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (0.13 g, 0.58 mmol), potassium carbonate (0.12 g, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (159 mg, 66%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 348.1 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (180 mg, 78%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (155 mg, 66%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4,6-dimethylpyrimidine (1.03 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.80 g, 58%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(1H-indol-3-yl)butyl 4-methylbenzenesulfonate (200 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (126 mg, 60%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (216 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (114 mg, 50%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (219 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 63%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (177 mg, 80.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (148 mg, 66%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (191 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (167 mg, 82%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (208 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (132 mg, 60.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (211 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (144 mg, 65%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (170 mg, 80%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (152 mg, 70.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-methoxy-6-methylpyrimidine (1.14 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.75 g, 50.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • Step 2) 3-(4-(4-(4-methoxy-6-methylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methoxy-6-methyl-2-(piperazin-1-yl)pyrimidine (121 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (147 mg, 63%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methoxy-6-methyl-2-(piperazin-1-yl)pyrimidine (121 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (130 mg, 57%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-cyanopyrimidine (1.00 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (0.81 g, 60%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (186 mg, 85%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (156 mg, 70%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 69%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (130 mg, 60%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloropyrimidine-4-carboxamide (1.13 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.04 g, 70.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (180 mg, 78%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 62%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (188 mg, 85%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.1 mol) in acetonitrile (15 mL) to give the title compound as a white solid (157 mg, 70%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-(trifluoromethyl)pyrimidine (1.31 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as yellow oil (1.25 g, 75%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 81.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (132 mg, 53%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (208 mg, 88.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (146 mg, 61%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-5-fluoropyrimidine (0.95 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.72 g, 55%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 5-fluoro-2-(piperazin-1-yl)pyrimidine (106 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (131 mg, 60%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 5-fluoro-2-(piperazin-1-yl)pyrimidine (106 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (135 mg, 64%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using ethyl 2-bromo-4-methylthiazole-5-carboxylate (1.80 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.65 g, 90%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • Step 2) ethyl 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (211 mg, 82%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (200 mg, 80%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (196 mg, 75%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (205 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (195 mg, 77%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-bromo-4-methylthiazole-5-carboxamide (1.60 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.59 g, 98%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 227.0 [M+H] + .
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (210 mg, 87%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 85%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 81%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (139 mg, 59%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-bromo-4-methylthiazole-5-carbonitrile (1.46 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.47 g, 98.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (194 mg, 84%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (188 mg, 85%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (182 mg, 78%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (181 mg, 80%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 5 of example 1, using 2-chloropyrimidine-4-carboxamide (1.13 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and 2-methylpiperazine (1.44 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.03 g, 65.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(3-methylpiperazin-1-yl)pyrimidine-4-carboxamide (128 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (163 mg, 70.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(3-methylpiperazin-1-yl)pyrimidine-4-carboxamide (128 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (164 mg, 68.0%).
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos.
  • the synaptosomes (150 ⁇ g) prepared from the rat brain were incubated at 37° C. for 15 minutes with 0.1 ⁇ Ci [ 3 H]5-HT in the absence or presence of the test compound or the reference compound in a buffer solution containing 106.2 mM NaCl, 4.5 mM KCl, 2.25 mM MgSO 4 , 1.08 mM NaH 2 PO 4 , 22.5 mM NaHCO 3 , 9.9 mM glucose, 9 ⁇ M EGTA and 45 ⁇ M ascorbic acid (pH 7.4).
  • the basal control activity was determined by incubating the same mixture at 4° C. for 15 minutes in the presence of 10 ⁇ M imipramine to block the uptake of 5-HT, which was taken as the standard reference compound and tested in each experiment at several concentrations to obtain an inhibition curve.
  • the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed twice with an ice-cold incubation buffer using a 96-sample cell harvester (Unifilter, Packard) to eliminate free [ 3 H]5-HT.
  • the filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
  • the experimental results were expressed as a percent inhibition of the control uptake of [ 3 H]5-HT.
  • Human HEK-293 cell homogenates (36 ⁇ g protein) were incubated at 22° C. for 60 minutes with 0.3 nM [ 3 H]8-OH-DPAT (Perkin-Elmer) in the absence or presence of the test compound in a buffer solution containing 50 mM Tris-HCl (pH 7.4), 10 mM MgSO 4 , 0.5 mM EDTA, 2 ⁇ g/ml aprotinine.
  • the non-specific binding value was determined by incubating the same mixture in the presence of 10 ⁇ M 8-OH-DPAT, which was used as the standard reference compound and tested in each experiment at several concentrations to obtain a competition curve.
  • the samples were filtered rapidly under vacuum through glass fiber filter (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard).
  • the filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
  • the experimental results were expressed as a percent inhibition of the control radioligand specific binding, and Ki was the inhibition constant.
  • Binding assay of [ 3 H] 8-OH-DPAT (0.3 nM) with 5-HT 1A , receptor in human HEK-293 cell was tested by scintillation proximity assay of membrane.
  • the test compounds were required to be tested at least three times in the case of the concentration thereof being greater than 6 log, and the obtained data were subjected to a nonlinear regression analysis via a curve of Hill equation, to obtain IC 50 value, and then calculated by ChengPrusoff equation to obtain Ki value.
  • the experimental results of the binding affinity of the compounds provided herein for 5-HT 1A receptor were showed in Table 2.
  • Cell membrane homogenates (24 ⁇ g protein) were incubated at 22° C. for 60 minutes with 0.3 nM [3H]methyl-spiperone in the absence or presence of the test compound in a buffer solution containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2 and 1 mM EDTA.
  • the non-specific binding value was determined by incubating the same mixture in the presence of 10 ⁇ M (+)butaclamol.
  • the samples were filtered rapidly under vacuum through glass fiber filter (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard).
  • the filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
  • the experimental results were expressed as a percent inhibition of the control radioligand specific binding, and Ki was the inhibition constant.
  • the standard reference compound was (+)butaclamol, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC 50 was calculated, and then Ki value was calculated by ChengPrusoff equation.
  • the experimental results of the binding affinity of the compounds provided herein for D 2S receptor were showed in Table 3.
  • the animals were administered with a dose of 5 mg/kg, and 0.3 mL of blood was collected at the time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after drug administration (the time point of drug administration was set as 0 h). All the blood samples were processed to separate plasma by centrifugation at 3000 rpm or 4000 rpm for 10 minutes. The plasma was collected and stored at ⁇ 20° C. or ⁇ 70° C. until LC/MS/MS analysis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Addiction (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Provided herein are novel heteroaryl compounds, pharmaceutically acceptable salts and pharmaceutical formulations thereof for selectively inhibiting serotonin reuptake and/or acting as 5-HT1A receptor agonists. Also provided herein are pharmaceutical compositions comprising the heteroaryl compounds and methods of using the pharmaceutical compositions in treating central nervous system (CNS) dysfunction in a mammal, especially a human being.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This is a U.S. national stage application of the International Patent Application No. PCT/CN2014/083135, filed 28 Jul. 2014, which claims priority to Chinese Patent Application No. 201310322334.6, filed 29 Jul. 2013, both of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention belongs to the field of pharmaceutical technology, and more specifically relates to novel compounds, compositions and methods of use thereof for treating central nervous system dysfunction. Particularly, provided herein are substituted heteroaryl compounds acting as 5-serotonin reuptake inhibitors and/or 5-HT1A receptor agonists.
BACKGROUND OF THE INVENTION
Serotonin, a neurotransmitter that carries signal in the brain and nerves, plays a very important role in central nervous system (CNS) dysfunction, especially in anxiety, depression, aggression and impulsivity. Regulation of the central nervous system dysfunction is possible either by antagonistic or agonistic action on a certain type of the serotonin receptors. To date, at least 14 different serotonin receptors have been identified. These receptors can be divided into distinct families—denoted 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7, with subtypes in each family denoted by letters such as a, b and c. Central serotonergic neurons are located in the raphe nuclei in the brain stem. The 5-HT1A receptor is a G-protein-coupled receptor widely distributed in regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus, and hypothalamus. In these cortico-limbic regions, 5-HT1A is distributed post-synaptically. The 5-HT1A receptor also serves as the predominant (somatodendritic) autoreceptor of the raphe nuclei, reducing the firing rate of neurons (the amount of serotonin released per action potential), the synthesis of the neurotransmitter, and thus by implication, the serotonergic activity of its projection areas. Activation of the presynaptic 5-HT1A, receptor may also indirectly reduce serotonergic transmission through the inhibition of tyrosine hydroxylase synthesis, as well as the activity of glutamatergic pathway that originates in the medial prefrontal cortex and projects to the raphe nuclei (Jonathan Savitz et al., “5-HT1A receptor function in major depressive disorder,” Prog. Neurobiol., 2009, 88(1): 17-31).
Depression is the most important of all therapeutic indications related to 5-HT disorder since it is the fourth leading burdensome disease in the world according to the World Health Organization. By 2020, depression is projected to rank second in disability-adjusted life years (Bromet E et al., “Cross-national epidemiology of DSM-IV major depressive episode,” BMC Med., 2011, 9: 90).
Historically, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) revolutionized the pharmacologic treatment of mood disorders in the 1950s, mostly by blocking neurotransmitter (dopamine, norepinephrine, and serotonin). However, the non-selectivity and undesirable side effect eventually limited their use. In 1980s, the discovery of selective serotonin reuptake inhibitors (SSRIs) changed the landscape. As a class, the SSRIs boast similar efficacy compared to the TCAs, and an improved AE profile with less tendency for toxicity in overdose (Sarko J, “Andidepressant, old and new. A review of their adverse effects and toxicity in overdose,” Emerg. Med. Clin North Am., 2000, 18 (4): 637-54).
Conventional SSRIs therapeutically increase available serotonin by inhibiting its reuptake and modulating its transmission. Administration of SSRIs also pleiotropically stimulates pre-synaptic 5-HT1A autoreceptors, which acutely decreases the release of serotonin and subsequently reduces serotonin concentrations in the synapse. After chronic administration, the stimulation of the 5-HT1A autoreceptors is overcome via desensitization and the SSRIs is able to normalize serotonergic transmission. It is postulated that this stimulation of the autoreceptor is the causative factor in the delayed therapeutic effect of the SSRIs (Celada P et al., “The therapeutic role of 5-HT1A and 5-HT2A receptors in depression,” J Psychiatry Neurosci., 2004, 29(4): 252-65). Thus, overriding the negative feedback effect of 5-HT1A autoreceptors antagonists holds the promise of increasing and accelerating clinical antidepressant effects.
Compared to SSRIs, 5-HT1A receptor agonists or partial agonists act directly on postsynaptic serotonin receptors to increase serotonin neurotransmission during the SSRI latency effect period. Feiger and Wilcox demonstrated that the buspirone and gepirone were clinically effective 5-HT1A partial agonists (Feiger, A, Psychopharmacol. Bull., 1996, 32: 659-65). The addition of buspirone to standard SSRI treatment produced a marked improvement in patients previously unresponsive to standard treatment for depression (Dimitriou, E. J., Clin. Psychopharmacol., 1998, 18: 465-9).
Provided herein are novel compounds believed to have clinical use in treating CNS disorders through selectively inhibiting serotonin reuptake and/or acting as 5-HT1A receptor agonists. The compounds disclosed herein are also believed to provide an improvement in potency, pharmacokinetic properties, and/or toxicity profile over certain counterparts found in the art.
SUMMARY OF THE INVENTION
This section merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects are described more fully below. All the documents cited in the present specification are hereby incorporated herein by reference in their entireties. Where the disclosure of the present specification is inconsistent with a patent, application, or publication incorporated by reference, the disclosure of the present specification shall prevail.
Provided herein are novel compounds acting as selective serotonin reuptake inhibitors and/or the 5-HT1A receptor agonists. The compounds can be used to manufacture medicaments for the treatment of human central nervous system (CNS) dysfunction, such as depression, anxiety disorder and bipolar disorder.
Provided herein also are methods for preparing the novel compounds disclosed herein and pharmaceutical compositions containing the compounds.
In one aspect, provided herein are compounds having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure US09598401-20170321-C00001
wherein
X is O, S or NH;
Y1 is CH or N;
Y2 is CR2 or N;
Y3 is CR3 or N;
Y4 is CR4 or N;
E is N or CH;
Figure US09598401-20170321-P00001
is either a single bond or a double bond, provided that: (1) when
Figure US09598401-20170321-P00001
is a single bond, G is CH or N; or (2) when
Figure US09598401-20170321-P00001
is a double bond, G is C;
Ar is
Figure US09598401-20170321-C00002
wherein each W is independently O, S or NH;
each Rx is independently D, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, —NR11R11a, —OR10, —(C1-C6 alkylene)-NR11R11a, (C1-C6 alkylene)-OR10, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a or —(C1-C6 alkylene)-aryl, or two Rx on two adjacent ring carbon atoms, together with the ring carbon atoms to which they are attached, form a C3-C6 carbocyclic or 3-6 membered heterocyclic ring;
k is 0, 1, 2, 3 or 4;
each of R1, R2, R3 and R4 is independently H, D, F, Cl, Br, I, NO2, CN, —SCN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R5, R6 and R7 is independently H, D, F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, -alkylene-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R8 is independently H, D, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, wherein each of alkenyl, alkynyl, alkoxy and cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R9 is independently D, F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R10 is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R11 and R11a is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, or R11 and R11a, together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene and heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino; and
m is 3, 4, 5 or 6.
In one embodiment, the compounds disclosed herein have Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure US09598401-20170321-C00003
In another embodiment, each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl or (C1-C5 heteroaryl)-(C1-C4 alkylene)-, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl and (C1-C5 heteroaryl)-(C1-C4 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C6 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R8 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C10 cycloalkyl, wherein each of C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, C2-C10 heterocyclyl, C6-C10 aryl and C1-C9 heteroaryl.
In another embodiment, each R8 is independently H, D, C1-C4 alkyl, C1-C4 alkoxy or C3-C8 cycloalkyl, wherein each of C1-C4 alkoxy and C3-C8 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R9 is independently D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each R9 is independently D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R10 is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; and
each R11 and R11a is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C10 heterocyclic ring, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl and C2-C10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, the compounds disclosed herein have Formula (III):
Figure US09598401-20170321-C00004
wherein
each Rx is independently D, Cl, Me, —CF3, —OMe, OH or NH2;
k is 0, 1, 2, 3 or 4;
R1 is H, D, F, Cl, CN, —OR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl or C1-C5 heteroaryl, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl and C1-C5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each R10 is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl;
each R11 and R11a is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C7 heterocyclic ring; and
m is 3, 4, 5 or 6.
In another embodiment, the compounds disclosed herein have Formula (IV):
Figure US09598401-20170321-C00005
In another embodiment, R1 is H, D, F, Cl, CN, OH, NH2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2.
In another embodiment, each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)NH2, —CH2—C(═O)NH2, —C(═O)NMe2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2, with the proviso that at least one of R5, R6 and R7 is not H.
In another embodiment, the compounds disclosed herein have Formula (V):
Figure US09598401-20170321-C00006
wherein
R1 is H, D, F, Cl, CN, —OR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl or C1-C5 heteroaryl, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl and C1-C5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
R8 is H, D, C1-C4 alkyl or C1-C4 alkoxy;
R9 is D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each R10 is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl;
each R11 and R11a is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C7 heterocyclic ring; and
m is 3, 4, 5 or 6.
In another embodiment, R1 is H, D, F, Cl, CN, OH, NH2, Me, —CF3, —OMe or —NMe2.
In another embodiment, R8 is H, D, Me, Et, i-Pr, t-Bu or —OMe.
In another embodiment, R9 is D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)NH2, —C(═O)NMe2, Me, Et, —CF3 or —OMe.
In another aspect, provided herein is a pharmaceutical composition containing the compound disclosed herein.
In one embodiment, the pharmaceutical composition disclosed herein further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof.
In another embodiment, the pharmaceutical composition disclosed herein further comprises at least one therapeutic agent for central nervous system dysfunction, wherein the therapeutic agent for central nervous system dysfunction is an antidepressant, an antianxiety agent, a lithium agent of mood stabilizer, an atypical antipsychotic agent, an antiepileptic agent, an anti-Parkinson agent, a selective serotonin reuptake inhibitor, a 5-HT1A receptor agonist, a central nervous system stimulant, a nicotine antagonist or a combination thereof.
In another embodiment, the therapeutic agent is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, vestipitant, chlordiazepoxide, perphenazine or a combination thereof.
In another aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal, including a human being.
In another aspect, provided herein is a method of preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal comprising administrating a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein to the mammal, including a human being.
In another aspect, provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, treating or lessening the severity of a central nervous system dysfunction in a mammal, including a human being.
In one embodiment, the central nervous system dysfunction is depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom or premenstrual tension syndrome.
In another aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for selectively inhibiting serotonin reuptake.
In another aspect, provided herein is a method of selectively inhibiting serotonin reuptake with the compound or the pharmaceutical composition disclosed herein.
In another aspect, provided herein is the compound or the pharmaceutical composition disclosed herein for use in selectively inhibiting serotonin reuptake.
In another aspect, provided herein are methods for preparation, separation and purification of the compounds represented by Formula (I), (II), (III), (IV) or (V).
Biological test results indicate that the compounds provided herein can be used as preferred selective serotonin reuptake inhibitors and/or 5-HT1A receptor agonists.
Any embodiment disclosed herein can be combined with other embodiments as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention. In addition, any technical feature in one embodiment can be applied to the corresponding technical feature in other embodiment as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention.
The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION Definitions and General Terminology
All the documents cited herein are incorporated by reference in their entireties, and if the meanings expressed in the documents are different from those in the invention, the expressions in the invention will control. In addition, the terms and phases used in the invention have the general meanings recognized by a person skilled in the art. Even so, the invention still tries to expound and explain the terms and phases as detailed as possible. If the terms and phases mentioned herein are not consistent with the well-known meanings, the meanings expressed in the invention will control. Regardless of whether the terms discussed appear alone or in combination, the definitions described herein are applicable.
For purposes disclosed herein, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference in their entireties.
The grammatical articles “one”, “a”, “an” and “the”, as used herein, are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article. By way of example, “a component” means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
As described herein, compounds disclosed herein may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses and species of the invention.
The term “optional” or “optionally” refers to that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optional bond” means that the bond may or may not be present, and that the description includes single, double or triple bonds.
The term “substituted” refers to the replacement of one or more hydrogen groups in a given structure with the group of a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
The term “unsubstituted” refers to a specified group without substituents.
The term “optionally substituted with . . . ” is used interchangeably with the term “unsubstituted or substituted with . . . ”, i.e., the given structure is unsubstituted or substituted with one or more substituents described herein. Some non-limiting examples of the substituents include D, F, Cl, N3, —CN, —OH, —SH, —NH2, alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
The term “unsaturated” refers to a moiety having one or more units of unsaturation.
The term “comprising” is an open-ended expression, which includes the content specified in the invention, but does not exclude other aspects.
At various places in the present specification, substituents of the compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
At various places in the present specification, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
The term “halogen” or “halo”, which may be used interchangeably herein, refers to F, Cl, Br or I.
The term “alkyl” or “alkyl group” refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms. In another embodiment, the alkyl group contains 1-6 carbon atoms. In still another embodiment, the alkyl group contains 1-4 carbon atoms. In yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group is optionally substituted with one or more substituents described herein.
Some non-limiting examples of the alkyl group include methyl (Me, —CH3), ethyl (Et, —CH2CH3), n-propyl (n-Pr, —CH2CH2CH3), isopropyl (i-Pr, —CH(CH3)2), n-butyl (n-Bu, —CH2CH2CH2CH3), isobutyl (i-Bu, —CH2CH(CH3)2), sec-butyl (s-Bu, —CH(CH3)CH2CH3), tert-butyl (t-Bu, —C(CH3)3), n-pentyl (—CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl (—CH2CH2CH(CH3)2), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), n-hexyl (—CH2CH2CH2CH2CH2CH3), 2-hexyl (—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.
The term “alkylene” refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms. In another embodiment, the alkylene group contains 1-4 carbon atoms. In still another embodiment, the alkylene group contains 1-3 carbon atoms. In yet another embodiment, the alkylene group contains 1-2 carbon atoms. The alkylene group is exemplified by methylene (—CH2—), ethylene (—CH2CH2—), isopropylene (—CH(CH3)CH2—), and the like. The alkylene group is optionally substituted with one or more substituents described herein.
The term “alkenyl” refers to a linear or branched chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl group is optionally substituted with one or more substituents described herein, and includes groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In one embodiment, the alkenyl group contains 2-8 carbon atoms. In another embodiment, the alkenyl group contains 2-6 carbon atoms. In still another embodiment, the alkenyl group contains 2-4 carbon atoms. Some non-limiting examples of the alkenyl group include ethenyl or vinyl (—CH═CH2), allyl (—CH2CH═CH2), and the like. The alkenyl group is optionally substituted with one or more substituents described herein.
The term “alkynyl” refers to a linear or branched-chain monovalent hydrocarbon group of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl group is optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms. In another embodiment, the alkynyl group contains 2-6 carbon atoms. In still another embodiment, the alkynyl group contains 2-4 carbon atoms. Some non-limiting examples of the alkynyl group include ethynyl (—C≡CH), propargyl (—CH2C≡CH), 1-propynyl (—C≡C—CH3), and the like. The alkynyl group is optionally substituted with one or more substituents described herein.
The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom, wherein the alkyl group is as defined herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In still another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
Some non-limiting examples of the alkoxy group include methoxy (MeO, —OCH3), ethoxy (EtO, —OCH2CH3), 1-propoxy (n-PrO, n-propoxy, —OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, —OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, —OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, —OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, —OC(CH3)3), 1-pentoxy (n-pentoxy, —OCH2CH2CH2CH2CH3), 2-pentoxy (—OCH(CH3)CH2CH2CH3), 3-pentoxy (—OCH(CH2CH3)2), 2-methyl-2-butoxy (—OC(CH3)2CH2CH3), 3-methyl-2-butoxy (—OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (—OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (—OCH2CH(CH3)CH2CH3), and the like.
The term “haloalkyl” or “haloalkoxy” refers to an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and alkoxy group are as defined herein. Some non-limiting examples of the haloalkyl group and the haloalkoxy group include chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like. The haloalkyl group or the haloalkoxy group is optionally substituted with one or more substituents described herein.
The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”, wherein the amino group is independently substituted with one or two alkyl groups, respectively. In one embodiment, the alkylamino group is lower alkylamino group having one or two alkyl groups of 1 to 6 carbon atoms, which are attached to a nitrogen atom. In another embodiment, the alkylamino group is lower alkylamino group having 1 to 4 carbon atoms. Some non-limiting examples of the alkylamino group include monoalkylamino or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.
The term “alkylthio” refers to a group containing a linear or branched alkyl group of 1 to 10 carbon atoms attached to a divalent sulfur atom. In one embodiment, the alkylthio group is lower alkylthio group having 1 to 4 carbon atoms. Some non-limiting examples of the alkylthio group include methylthio (CH3S—). The alkylthio group is optionally substituted with one or more substituents described herein.
The term “cycloalkyl” refers to a saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system, wherein the bicyclic or tricyclic ring system may include fused ring, bridged ring and spiro ring. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms. In another embodiment, the cycloalkyl group contains 3-8 carbon atoms. In still another embodiment, the cycloalkyl group contains 3-6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The term “cycloalkylalkylene” refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and cycloalkyl group are as defined herein. In one embodiment, the cycloalkylalkylene group is lower cycloalkylalkylene group in which the cycloalkyl group is attached to an alkyl group having 1 to 6 carbon atoms. In another embodiment, the cycloalkyl group is attached to an alkyl group having 1 to 4 carbon atoms. In still another embodiment, the cycloalkyl group is attached to an alkyl group having 1 to 3 carbon atoms. The cycloalkylalkylene group is optionally substituted with one or more substituents described herein.
The term “heteroatom” refers to one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including any oxidized form of nitrogen (N), sulfur (S) or phosphorus (P); the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used interchangeably herein refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom as defined herein and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the rest of the molecule. In some embodiments, the “heterocycle”, “heterocyclyl” or “heterocyclic” group is a monocycle having 3 to 8 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, or PO or PO2, with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 12 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or SO2, or PO or PO2). The “heterocycle”, “heterocyclyl” or “heterocyclic” group is optionally substituted with one or more substituents described herein.
The heterocyclyl may be a carbon radical or heteroatom radical. Some non-limiting examples of the heterocyclyl group include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl. Examples of the heterocyclyl group wherein two ring carbon atoms are substituted with oxo (═O) moieties are pyrimidindionyl and 1,1-dioxo-thiomorpholinyl.
The term “heterocyclylalkylene” refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the alkyl group and heterocyclyl group are as defined herein. In one embodiment, the heterocyclylalkylene group is lower heterocyclylalkylene group in which the heterocyclyl group is attached to an alkyl group having 1 to 6 carbon atoms. In another embodiment, the heterocyclyl group is attached to an alkyl group having 1 to 4 carbon atoms. Some non-limiting examples of the heterocyclylalkylene group include 2-pyrrolidinoethyl, and the like. The heterocyclylalkylene group is optionally substituted with one or more substituents described herein.
The term “aryl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, preferably, 6 to 10 ring members, and more preferably 6 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The aryl group is generally, but not necessarily bonded to the parent molecule through an aromatic ring of the aryl group. The term “aryl” may be used interchangeably with the term “aryl ring” or “aromatic ring”. Some non-limiting examples of the aryl group include phenyl, naphthyl and anthracene. The aryl group is optionally substituted with one or more substituents described herein.
The term “arylalkylene” refers to an alkyl group substituted with one or more aryl groups, wherein the alkyl group and aryl group are as defined herein. In one embodiment, the arylalkylene group is lower arylalkylene group in which the aryl group is attached to an alkyl group having 1 to 6 carbon atoms. In another embodiment, the arylalkylene group is “phenylalkylene” containing alkyl groups of 1 to 4 carbon atoms. Some non-limiting examples of the arylalkylene group include benzyl, diphenylmethyl, phenylethyl, and the like. The arylalkylene group is optionally substituted with one or more substituents described herein.
The term “heteroaryl” refers to monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 14 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 5 to 7 ring members. The heteroaryl group is generally, but not necessarily bonded to the parent molecule through an aromatic ring of the heteroaryl group. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic ring”. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
Some non-limiting examples of the heteroaryl group include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, and 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, and the like.
The term “heteroarylalkylene” refers to an alkyl group substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl group are as defined herein. In one embodiment, the heteroarylalkylene group is lower heteroarylalkylene groups in which the heteroaryl group is attached to an alkyl group having 1 to 6 carbon atoms. In another embodiment, the heteroaryl group is attached to an alkyl group having 1 to 4 carbon atoms. Some non-limiting examples of the heteroarylalkylene group include 2-pyridylmethyl, 3-furylethyl, and the like. The heteroarylalkylene group is optionally substituted with one or more substituents described herein.
The term “carbonyl”, whether used alone or with other terms, refers to —(C═O)—.
The term “acyl” refers to —(C═O)—R.
The term “amido” refers to —NH(C═O)—R.
The term “carbamoyl” refers to —C(═O)NH2.
The term “azido” refers to —N3. The azido group can be attached to other groups, for example, to methyl to form methylazide (MeN3), or to phenyl to form phenylazide (PhN3).
As described herein, a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the rings to which it is attached. For example, Figure a represents possible substitution in any of the position on the ring B.
Figure US09598401-20170321-C00007
The term “spirocyclyl”, “spirocyclic”, “spiro bicyclyl” or “spiro bicyclic” as used interchangeably herein refers to a ring system wherein a ring originating from a particular annular carbon of another ring. For example, as depicted below in Figure c and Figure d, ring A and ring B share a carbon atom between the two saturated ring system, which terms as a “spirocyclyl” or “spiro bicyclyl”. Each ring in the spiro bicyclyl can be either a carbocyclyl or a heterocyclyl. Some non-limiting examples of the spiro bicyclyl group include 4-oxaspiro[2.4]hept-6-yl, and (R)-4-azaspiro[2.4]hept-6-yl. The spiro bicyclyl group is optionally substituted with one or more substituents described herein.
Figure US09598401-20170321-C00008
The term “fused bicyclic ring”, “fused cyclic”, “fused bicyclyl” or “fused cyclyl” as used interchangeably herein refers to a bridged ring system in which two rings share a common C—C bond. For example, as depicted below in Figure e, Figure f and Figure g, two five-membered rings (Figure e), two six-membered rings (Figure f), and a five-membered ring and a six-membered ring (Figure g) share a common C—C bond. Such a ring system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). Each ring in the fused bicyclic ring system is independently carbocyclic ring or heterocyclic ring.
Figure US09598401-20170321-C00009
Some non-limiting examples of the fused bicyclyl group include hexahydrofuro[2,3-b]furan-3-yl, hexahydrofuro[3,2-b]furan-3-yl, octahydrocyclopenta[c]pyrrol-5-yl, octahydropentalen-2-yl, octahydro-1H-isoindol-5-yl, and the like. The fused bicyclyl group is optionally substituted with one or more substituents described herein.
The term “stereoisomer” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
The term “diastereoisomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
The term “enantiomer” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
The term “racemate” or “racemic mixture” refers to an equimolar mixture of two enantiomeric species devoid of optical activity.
The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
Stereochemical definitions and conventions used herein generally follow Parker et al., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel et al., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.
Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert et al., Elsevier, Oxford, UK, 2012); Eliel et al., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen et al., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972). Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
The term “pharmaceutically acceptable” refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response or other problem or complication commensurate with a reasonable benefit/risk ratio, and effective for their intended purpose.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
The term “prodrug” refers to a compound that is transformed in vivo into a compound of Formula (I). Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation of the prodrug form in blood or tissue to the parent form. Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form. Other prodrug forms include phosphates, such as those phosphate compounds derived from the phosphonation of an OH group on the parent compound. A thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al, Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
A “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. The metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including metabolites produced by a process comprising contacting a compound disclosed herein with a mammal for a sufficient time period.
The term “pharmaceutically acceptable salt” refers to a salt which is, within the scope of sound medical judgement, suitable for contacting tissues of human and lower animals without showing excessive toxicity, irritation and anaphylactic response, and is commensurate to reasonable effect/risk ratio. The pharmaceutically acceptable salt is well known in the art. For example, S. M. Berge, et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1.
Some non-limiting examples of pharmaceutically acceptable salts derived from nontoxic acids include acetate, adipate, alginate, citrate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, maleate, laurate, laurylsulfate, malate, malonate, methanesulfonate, nicotinate, 2-napsylate, oxalate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, stearate, thiocyanate, phosphate, glutamate, bicarbonate, p-tosylate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-C4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further examples of the pharmaceutically acceptable salt include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-C8 sulfonate and aryl sulfonate.
A “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of solvents that form the solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
The term “hydrate” can be used when said solvent is water. In some embodiments, one solvent molecule is associated with one molecule of the compounds disclosed herein, such as a hydrate. In other embodiments, more than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a dihydrate. In still other embodiments, less than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a hemihydrate. Furthermore, all the solvates of the invention retain the biological effectiveness of the non-hydrate form of the compounds disclosed herein.
The term “protecting group” or “PG” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Examples of suitable amino-protecting groups include acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethylenoxycarbonyl (Fmoc) and benzyl. Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Examples of suitable hydroxy-protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Examples of common carboxy-protecting groups include —CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.
The term “preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
The term “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the condition, age, weight, gender etc. of the subject to be treated.
“Treating” or “treatment” of a disease state includes: (i) preventing the disease state, i.e., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, (ii) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or (iii) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
DESCRIPTION OF COMPOUNDS OF THE INVENTION
Disclosed herein are heteroaryl compounds, pharmaceutically acceptable salts thereof, pharmaceutical formulations thereof and compositions thereof, which are acting as selective serotonin reuptake inhibitors and/or 5-HT1A receptor agonists and have potential therapeutic uses for the treatment of human central nervous system (CNS) dysfunction, such as depression, anxiety disorder or bipolar disorder.
In one aspect, provided herein are compounds having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure US09598401-20170321-C00010
wherein
X is O, S or NH;
Y1 is CH or N;
Y2 is CR2 or N;
Y3 is CR3 or N;
Y4 is CR4 or N;
E is N or CH;
Figure US09598401-20170321-P00001
is either a single bond or a double bond, provided that: (1) when
Figure US09598401-20170321-P00001
is a single bond, G is CH or N; or (2) when
Figure US09598401-20170321-P00001
is a double bond, G is C;
Ar is
Figure US09598401-20170321-C00011
wherein each W is independently O, S or NH;
each Rx is independently D, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, —NR11R11a, —OR10, —(C1-C6 alkylene)-NR11R11a, —(C1-C6 alkylene)-OR10, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a or —(C1-C6 alkylene)-aryl, or two Rx on two adjacent ring carbon atoms, together with the ring carbon atoms to which they are attached, form a C3-C6 carbocyclic or 3-6 membered heterocyclic ring;
k is 0, 1, 2, 3 or 4;
each of R1, R2, R3 and R4 is independently H, D, F, Cl, Br, I, NO2, CN, —SCN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R5, R6 and R7 is independently H, D, F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, -alkylene-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R8 is independently H, D, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, wherein each of alkenyl, alkynyl, alkoxy and cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R9 is independently D, F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R10 is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R11 and R11a is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, or R11 and R11a, together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene and heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino; and
m is 3, 4, 5 or 6.
In one embodiment, the compounds disclosed herein have Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure US09598401-20170321-C00012
In another embodiment, each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl or (C1-C5 heteroaryl)-(C1-C4 alkylene)-, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl and (C1-C5 heteroaryl)-(C1-C4 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C6 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R8 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C10 cycloalkyl, wherein each of C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, C2-C10 heterocyclyl, C6-C10 aryl and C1-C9 heteroaryl.
In another embodiment, each R8 is independently H, D, C1-C4 alkyl, C1-C4 alkoxy or C3-C8 cycloalkyl, wherein each of C1-C4 alkoxy and C3-C8 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R9 is independently D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, each R9 is independently D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
In another embodiment, each R10 is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; and
each R11 and R11a is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C10 heterocyclic ring, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl and C2-C10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
In another embodiment, the compounds disclosed herein have Formula (III):
Figure US09598401-20170321-C00013
wherein
each Rx is independently D, Cl, Me, —CF3, —OMe, OH or NH2;
k is 0, 1, 2, 3 or 4;
R1 is H, D, F, Cl, CN, —OR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl or C1-C5 heteroaryl, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl and C1-C5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each R10 is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl;
each R11 and R11a is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C7 heterocyclic ring; and
m is 3, 4, 5 or 6.
In another embodiment, the compounds disclosed herein have Formula (IV):
Figure US09598401-20170321-C00014
In another embodiment, R1 is H, D, F, Cl, CN, OH, NH2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2.
In another embodiment, each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)NH2, —CH2—C(═O)NH2, —C(═O)NMe2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2, with the proviso that at least one of R5, R6 and R7 is not H.
In another embodiment, the compounds disclosed herein have Formula (V):
Figure US09598401-20170321-C00015
wherein
R1 is H, D, F, Cl, CN, —OR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl or C1-C5 heteroaryl, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl and C1-C5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
R8 is H, D, C1-C4 alkyl or C1-C4 alkoxy;
R9 is D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each R10 is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl;
each R11 and R11a is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C7 heterocyclic ring; and
m is 3, 4, 5 or 6.
In another embodiment, R1 is H, D, F, Cl, CN, OH, NH2, Me, —CF3, —OMe or —NMe2.
In another embodiment, R8 is H, D, Me, Et, i-Pr, t-Bu or —OMe.
In another embodiment, R9 is D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)NH2, —C(═O)NMe2, Me, Et, —CF3 or —OMe.
In another embodiment, the compounds disclosed herein have one of the following structures:
Figure US09598401-20170321-C00016
Figure US09598401-20170321-C00017
Figure US09598401-20170321-C00018
Figure US09598401-20170321-C00019
Figure US09598401-20170321-C00020
Figure US09598401-20170321-C00021
Figure US09598401-20170321-C00022
Figure US09598401-20170321-C00023
Figure US09598401-20170321-C00024
Figure US09598401-20170321-C00025
Figure US09598401-20170321-C00026
Figure US09598401-20170321-C00027
Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds disclosed herein are within the scope of the invention.
To be more specific, in one aspect, the invention includes all suitable isotopic variations of the compounds disclosed herein. An isotopic variation of the compounds disclosed herein is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature with the most abundant isotope(s) being preferred. Examples of isotopes that can be incorporated into the compounds disclosed herein include the isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine, such as H2, H3, C11, C13, C14, N15, O17, O18, S35, F18 and Cl36, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as H3 or C14 is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., H3, and carbon-14, i.e., C14, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., H2, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds disclosed herein can generally be prepared by conventional procedures such as using appropriate isotopic variations of suitable reagents.
Also part of the invention are those compounds wherein at least one atom has been replaced by an isotope of a different atom that can be used in vivo imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography (PET). Examples for such derivatives usable in SPECT studies are compounds wherein a Tc99m, In111, Rb82, Cs137, I123, Ga67, Ir192 or Tl201 and preferably I123 has been introduced (for iodination see e.g.: Coenen et al., Radioiodination Reactions for Pharmaceuticals, Compendium for Effective Synthesis Strategies, Springer, Dordrecht, 2006), while for PET applications C11, N13, O15, F18, Rb82, Sr82, and preferably F18 (Coenen et al., Fluorine-18 labeling methods: Features and possibilities of basic reactions, Ernst Schering Res Found Workshop, 2007, Vol 62, p 15-50; Miller et al., Ang Chem Int Ed, 2008, Vol 47, p 8998) may be used.
In another aspect, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms, for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the compounds disclosed herein are within the scope of the invention.
In another aspect, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
In another aspect, N-oxides of the compounds disclosed herein are also within the scope of the invention and may be prepared by oxidation of the corresponding nitrogen base using a conventional oxidizing agent such as hydrogen peroxide in the presence of an acid such as acetic acid at an elevated temperature, or by reaction with a peracid such as peracetic acid in a suitable solvent, e.g. dichloromethane, ethyl acetate or methyl acetate, or in chloroform or dichloromethane with 3-chloroperoxybenzoic acid.
In another aspect, salts of the compounds disclosed herein include pharmaceutically acceptable salts thereof, as well as other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I), (II), (III), (IV) or (V) and/or for separating enantiomers of compounds of Formula (I), (II), (III), (IV) or (V).
If the compound disclosed herein is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha-hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.
If the compound disclosed herein is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Some non-limiting examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
COMPOSITION, FORMULATION AND ADMINISTRATION OF COMPOUNDS OF THE INVENTION
Provided herein is an pharmaceutical composition comprising the compound of Formula (I), (II), (III), (IV) or (V), or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, in admixture with at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.
Appropriate carriers, adjuvants and vehicles are well known to those of skill in the art and described in, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 2004, Lippincott, Williams & Wilkins, Philadelphia; Gennaro et al., Remington: The Science and Practice of Pharmacy, 2000, Lippincott, Williams & Wilkins, Philadelphia; and Rowe et al., Handbook of Pharmaceutical Excipients, 2005, Pharmaceutical Press, Chicago.
The compounds or compositions disclosed herein may be administered by any suitable means, including oral (including buccal and sublingual), topical, rectal, vaginal, transdermal, parenteral (intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous), intrapulmonary, intradermal, intrathecal, epidural and intranasal, as well as intralesional administration if desired for local treatment. The preferred method is oral administration, intraperitoneal or intravenous administration.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art.
Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol) and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solvent, dispersant, suspending agent or emulsifying agent, as well as sterile dispersant for reforming a sterile injectable solution or dispersion. The examples of suitable aqueous or nonaqueous carriers, diluents, solvents or media include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oil (such olive oil), injectable organic esters such as ethyl oleate and suitable mixtures thereof.
These compositions can further comprise excipients, such as preservative, wetting agent, emulsifying agent and dispersant. The use of various antibacterial agents and antifungal agents, such as nipagins, nautisan, phenol, sorbic acid, etc. can ensure effects of combating microorganisms. It is also desired to comprise isotonizing agents such as sugars, sodium chloride, etc. The use of substances for absorption delay, such as aluminum monostearate and gelatin, can achieve the prolonged absorption of injectable dosage form.
Besides active compounds, the suspensions can further comprise a suspending agent, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan, microcrystalline cellulose, meta-aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.
In some cases, it is desired to reduce the absorption rate of subcutaneously or intramuscularly administered drug for prolonging the effect of drug. This may be reached by using a liquid suspension of crystal or amorphous form with poor water solubility. Thus, the absorption rate of drug depends on its dissolution rate, while the dissolution rate depends on the size and form of crystal. Or, the delayed absorption of drug in parenteral administration may be reached by dissolving or dispersing the drug in an oil medium.
An injectable depot dosage form may be prepared by forming microcapsule substrate of drug in a biodegradable polymer such as polylactide-polyglycolide. The release rate of drug may be controlled according to the ratio of drug to polymer and the properties of the specifically used polymer. Other examples of biodegradable polymer comprise poly (orthoesters) and poly (anhydrides). The injectable depot dosage form can also be prepared by embedding drug in a liposome or microemulsion compatible to body tissues.
The injectable preparation may be sterilized by filtration using a bacterial filter or by incorporating a sterilizing agent in the form of a sterile solid composition, and the solid composition may be dissolved or dispersed in sterile water or other sterile injectable media before clinical application.
The compounds disclosed herein may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. In addition, ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention
The pharmaceutically acceptable compositions disclosed herein can be in the form of a rectal or vaginal suppository. These can be prepared by mixing the agent with the appropriate non-perfusion adjuvant. The mixture prepared this way is a solid at room temperature, but it becomes a liquid at rectal or vaginal temperature and releases the drug in the rectum or vagina. Such substances include cocoa fat, beeswax and polyethylene glycol.
For intranasal administration or administration by inhalation, the active compounds disclosed herein are conveniently delivered in the form of an aerosol spray from a pressurized container or a nebulizer or from a capsule using an inhaler or insufflators. In the case of a pressurized aerosol, a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas) and the dosage unit may be determined by providing a valve to deliver a metered amount. The medicament for pressurized container or nebulizer may contain a solution or suspension of the active compound, while for a capsule, it preferably should be in the form of powder. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound disclosed herein and a suitable powder base (e.g., lactose or starch).
Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains 20 μg to 1000 μg of the compound disclosed herein. The overall daily dose with an aerosol will be within the range 100 μg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.
It should be understood that the total amount per day of the compound or composition disclosed herein must be determined by a physician within the range of reliable medical decisions. As for any specific patient, the specific therapeutically amount must be determined based on various factors, including the diseases to be treated and severity thereof; the activity of the used specific compound; the used specific composition; the age, body weight, general health status, gender and food of patient; the administration time, route and excretory rate of the used specific compound; the duration of the treatment; the drug administered in combination or simultaneously with the specific compound; and similar factors well known in the art of medicine. For example, it is a common method in the art to increase gradually the dose of compound from a level lower than that for achieving desired therapeutical effects to a level enough to achieve the desired therapeutical effects. In general, the dose of a compound of Formula (I), (II), (III), (IV) or (V) for mammals especially human may be 0.1-1000 mg/kg body weight per day, preferably 1-100 mg/kg body weight per day. The administration may be once or several times a day, and each administration may include 1, 2 or 3 doses.
The compound of Formula (I), (II), (III), (IV) or (V) may either be administered alone or in combination with another therapeutically active compound, wherein the two compounds may either be administered simultaneously or sequentially. Some non-limiting examples of the therapeutically active compound which may advantageously be combined with the compounds of Formula (I), (II), (III), (IV) or (V) include sedatives or hypnotics, such as benzodiazepines; anticonvulsants, such as lamotrigine, valproic acid, topiramate, gabapentin, and carbamazepine; mood stabilizers such as lithium; dopaminergic drugs, such as dopamine agonists and L-Dopa; drugs to treat ADHD, such as atomoxetine; psychostimulants, such as modafinil, ketamine, methylphenidate and amphetamine; other antidepressants, such as mirtazapine, mianserin and buproprion; hormones, such as T3, estrogen, DHEA and testosterone; atypical antipsychotics, such as olanzapine and aripiprazole; typical antipsychotics, such as haloperidol; drugs to treat Alzheimer's diseases, such as cholinesterase inhibitors, memantine, and folate; S-Adenosyl-Methionine; immunomodulators, such as interferons; opiates, such as buprenorphins; angiotensin II receptor 1 antagonists (ATI antagonists); ACE inhibitors; statins; and alpha adrenergic antagonist, such as prazosin.
USES OF THE COMPOUNDS AND COMPOSITIONS OF THE INVENTION
The compounds and pharmaceutical compositions disclosed herein can be used in the manufacture of a medicament for preventing, treating or lessening the severity of a central nervous system dysfunction in mammals including humans, as well as for inhibiting serotonin reuptake and/or acting as 5-HT1A receptor agonists.
Specifically, amount of the compounds used in the compositions disclosed herein is efficient to inhibit serotonin reuptake detectably and selectively, and has agonistic action for 5-HT1A receptor. The compounds disclosed herein may be the agents used for treatment of the human central nervous system (CNS) dysfunction such as depression, anxiety.
The compounds disclosed herein may be used for, but not limited to, preventing, treating or lessening the severity of central nervous system dysfunction in mammals including humans by administering an effective amount of the compounds or compositions disclosed herein to patient. Such human central nervous system dysfunctions responsed to 5-HT receptor further include, but are not limited to, depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptom or premenstrual tension syndrome.
Besides being useful for human treatment, these compounds and compositions are also useful for veterinary treatment of companion animals, exotic animals and mammals of farm animals. In other embodiments, animals include horses, dogs and cats. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
SYNTHESIS OF COMPOUNDS
In order to describe the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but only provides the methods to practice the invention.
Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I), except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention.
Persons skilled in the art will recognize that the chemical reactions described herein may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described herein, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Tianjin Fucheng Reagent Chemical Factory, Wuhan Xinhuayuan Technology Development Co. Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.
Anhydrous THF, dioxane, toluene and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na2SO4 prior to use.
The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
Column chromatography was conducted using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. 1H NMR spectra were obtained by using CDCl3, d6-DMSO, CD3OD or d6-acetone solutions (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities were reported, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, were reported in Hertz (Hz).
Low-resolution mass spectral (MS) data were generally determined on Agilent 1200 or Agilent 6120 Series LC-MS (Column Type: Zorbax SB-C18, 2.1×30 mm, 3.5 micron, 6 min, and 0.6 mL/min flow rate). The mobile phase was 5-95% (0.1% formic acid in CH3CN) in (0.1% formic acid in H2O), and the generated chromatograms were monitored at 210/254 nm by UV detector with low response EFI mode (ESI).
Purity of compounds was assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm. Column was operated at 40° C.
The following abbreviations are used throughout the specification:
  • aq. aqueous solution
  • CH2Cl2, DCM dichloromethane
  • CDCl3 chloroform-d
  • DIEA, DIPEA diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMAP 4-dimethylaminopyridine
  • DMSO dimethyl sulfoxide
  • EtOAc, EA ethyl acetate
  • Et3N, TEA triethylamine
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylenebis(oxyethylenenitrilo)tetraacetic acid
  • g gram
  • h hour
  • H2SO4 sulfuric acid
  • HBTU O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • K2CO3 potassium carbonate
  • KI potassium iodide
  • KCl potassium chloride
  • MeOH, CH3OH methanol
  • MgSO4 magnesium sulfate
  • mL, ml milliliter
  • min minute
  • N2 nitrogen
  • RT, rt, r.t. room temperature
  • NaBH4 sodium borohydride
  • NH4Cl ammonia chloride
  • NaHCO3 sodium bicarbonate
  • NaH2PO4 sodium dihydrogen phosphate
  • NaCl sodium chloride
  • Na2SO4 sodium sulfate
  • PCC pyridinium chlorochromate
  • PE petroleum ether (60-90° C.)
  • THF tetrahydrofuran
  • Tri-HCl 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride
  • TsCl tosyl chloride
The following synthesis scheme describes the preparation of the compounds disclosed herein. Unless otherwise indicated, each R1, R5, R6, R7, R8 and R9 has the definitions as described herein.
Figure US09598401-20170321-C00028
Compound (8) can be prepared by the process illustrated in Scheme 1. Firstly, 6-hexanolactone (1) can be converted to compound (2) by alcoholysis with sulfuric acid as a catalyst and then oxidation in the presence of PCC. Then compound (2) can react with compound (3) to form compound (4) by Fischer indole cyclization in an alcoholic solvent such as ethanol, isopropanol or tert-butanol. Compound (4) can further react with a reducing agent such as lithium aluminum hydride to form compound (5) at a suitable temperature such as 40-120° C. The hydroxyl group of compound (5) can be converted to p-toluenesulfonate group to form compound (6), and then compound (6) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (8) by nucleophilic substitution.
Figure US09598401-20170321-C00029
Compound (8) can also be prepared by the process illustrated in Scheme 2. Firstly, Friedel-Crafts acylation reaction of compound (9) with chlorobutyryl chloride can give compound (10). Compound (10) can then react with a reducing agent such as sodium borohydride or lithium aluminum hydride to afford compound (11) in a suitable solvent such as tert-butanol or isopropanol. Then the hydroxyl group of compound (11) can be converted to p-toluenesulfonate group to form compound (6), and compound (6) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (8) by nucleophilic substitution.
Figure US09598401-20170321-C00030
Compound (16) can be prepared by the process illustrated in Scheme 3. Firstly, tetrahydropyrane (13) can react with compound (3) to give compound (14) by Fischer indole cyclization at a suitable temperature such as 40-120° C. Then the hydroxyl group of compound (14) can be converted to p-toluenesulfonate group to form compound (15), and compound (15) can further react with compound (7) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol or DMF to afford the objective compound (16) by nucleophilic substitution.
Figure US09598401-20170321-C00031
Compound (19) can be prepared by the process illustrated in Scheme 4. Firstly, compound (17) can be converted to compound (18) by reacting with anhydrous piperazine. Then nucleophilic substitution reaction of compound (18) with compound (6) can give the objective compound (19) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO and at a suitable temperature such as 30-100° C.
Figure US09598401-20170321-C00032
Compound (20) can be prepared by the process illustrated in Scheme 5. Nucleophilic substitution reaction of compound (17) with compound (15) can give the objective compound (20) in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine in a suitable solvent such as acetonitrile, tetrahydrofuran, ethanol, DMF or DMSO and at a suitable temperature such as 30-100° C.
The compounds, pharmaceutical compositions and applications thereof disclosed herein will be further illustrated in combination with the following examples.
EXAMPLES Example 1 3-(4-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
Figure US09598401-20170321-C00033
Step 1) ethyl 6-oxohexanoate
To a mixture of 6-hexanolactone (15.0 g, 0.13 mol) in ethanol (125 mL) was added concentrated sulfuric acid (1.1 mL) dropwise. The reaction mixture was heated to 80° C. and stirred for 24 hours. Then the reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted with ice water (150 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dried to obtain ethyl 6-hydroxyhexanoate (10.3 g).
To a solution of PCC (16.2 g, 75.5 mmol) in DCM (140 mL) was added a mixture of ethyl 6-hydroxyhexanoate (10.3 g, 64.3 mmol) in DCM (20 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 2 hours, and then EtOAc (100 mL) was added. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the title compound as a white solid (9.28 g, 45%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 159.3 [M+H]+.
Step 2) ethyl 4-(1H-indol-3-yl)butanoate
To a mixture of ethyl 6-oxohexanoate (1.0 g, 6.3 mmol) in ethanol (125 mL) was added phenylhydrazine (0.7 g, 6.8 mmol) at rt. The reaction mixture was heated to 80° C. and stirred for 20 hours. Then the reaction mixture was cooled to rt and concentrated in vacuo. The residue was diluted with ice water (100 mL) and extracted with EtOAc (150 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.63 g, 43.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 232.2 [M+H]+.
Step 3) 4-(1H-indol-3-yl)butan-1-ol
To a solution of ethyl 4-(1H-indol-3-yl)butanoate (0.29 g, 1.25 mmol) in THF (20 mL) was added lithium aluminum hydride (0.19 g, 5.08 mmol) in portions at 0° C. After the reaction mixture was stirred at rt for 1 hour, it was heated to 80° C. and stirred for 20 hours. Then the reaction mixture was cooled to 0° C., quenched with saturated aqueous sodium sulfate solution (1 mL) and diluted with EtOAc (150 mL). The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (0.18 g, 75%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 190.2 [M+H]+.
Step 4) 4-(1H-indol-3-yl)butyl 4-methylbenzenesulfonate
To a mixture of 4-(1H-indol-3-yl)butan-1-ol (0.36 g, 1.9 mmol) in DCM (20 mL) were added TEA (0.3 mL, 2.28 mmol) and TsCl (0.43 g, 2.28 mmol). After the reaction mixture was stirred at rt for 4 hours, it was quenched with water (100 mL). The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.42 g, 64.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 344.2 [M+H]+.
Step 5) 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine
To a mixture of 2-chloro-4,6-dimethoxypyrimidine (1.26 g, 7.2 mmol) in DMF (10 mL) were added potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol). The reaction mixture was heated to 100° C. and stirred for 10 hours. Then the reaction mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (v/v)=20/1) to give the title compound as yellow oil (1.05 g, 65.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 225.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 5.39 (s, 1H), 3.86 (s, 6H), 3.78 (t, J=4.9 Hz, 4H), 3.47 (t, J=5.0 Hz, 4H).
Step 6) 3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
To a mixture of 4-(1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.2 g, 0.58 mmol) and 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (0.13 g, 0.58 mmol) in acetonitrile (15 mL) were added potassium carbonate (0.12 g, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) under an nitrogen atmosphere. The reaction mixture was heated to 80° C. and stirred for 20 hours. Then the reaction mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as a white solid (149 mg, 65.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 396.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.95 (br s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 7.12-7.09 (m, 1H), 6.98 (t, J=1.8 Hz, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.82-3.78 (m, 4H), 2.79 (t, J=7.4 Hz, 2H), 2.47 (t, J=5.0 Hz, 4H), 2.42 (t, J=7.6 Hz, 2H), 1.78-1.72 (m, 2H), 1.67-1.61 (m, 2H).
Example 2 3-(4-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-5-methoxy-1H-indole
Figure US09598401-20170321-C00034
Step 1) ethyl 4-(5-methoxy-1H-indol-3-yl)butanoate
The title compound was prepared by the procedure described in step 2 of example 1, using ethyl 6-oxohexanoate (1.0 g, 6.3 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.2 g, 6.8 mmol) in ethanol (125 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.49 g, 30.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 262.2 [M+H]+.
Step 2) 4-(5-methoxy-1H-indol-3-yl)butan-1-ol
The title compound was prepared by the procedure described in step 3 of example 1, using ethyl 4-(5-methoxy-1H-indol-3-yl)butanoate (0.33 g, 1.27 mmol) and lithium aluminum hydride (0.19 g, 5.08 mmol) in THF (25 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (0.21 g, 75%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 220.2 [M+H]+.
Step 3) 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 4-(5-methoxy-1H-indol-3-yl)butan-1-ol (0.42 g, 1.9 mmol), TEA (0.3 mL, 2.28 mmol) and TsCl (0.43 g, 2.28 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.46 g, 65.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 374.1 [M+H]+.
Step 4) 3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-5-methoxy-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (216 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (148 mg, 60.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 426.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.98 (br s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 6.84 (dd, J=8.8, 2.2 Hz, 1H), 6.98 (s, 1H), 3.87 (s, 3H), 3.85 (s, 6H), 3.80 (t, J=5.0 Hz, 4H), 2.75 (t, J=7.3 Hz, 2H), 2.47 (t, J=4.9 Hz, 4H), 2.42 (t, J=7.6 Hz, 2H), 1.74-1.72 (m, 2H), 1.65-1.64 (m, 2H).
Example 3 5-Chloro-3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
Figure US09598401-20170321-C00035
Step 1) ethyl 4-(5-chloro-1H-indol-3-yl)butanoate
The title compound was prepared by the procedure described in step 2 of example 1, using ethyl 6-oxohexanoate (2.0 g, 12.6 mmol) and 4-chlorophenylhydrazine hydrochloride (2.4 g, 13.6 mmol) in ethanol (125 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.16 g, 35%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 266.2 [M+H]+.
Step 2) 4-(5-chloro-1H-indol-3-yl)butan-1-ol
The title compound was prepared by the procedure described in step 3 of example 1, using ethyl 4-(5-chloro-1H-indol-3-yl)butanoate (0.67 g, 2.54 mmol) with lithium aluminum hydride (0.39 g, 10.16 mmol) in THF (25 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (0.42 g, 74%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 224.2 [M+H]+.
Step 3) 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 4-(5-chloro-1H-indol-3-yl)butan-1-ol (0.43 g, 1.9 mmol), TEA (0.3 mL, 2.28 mmol) and TsCl (0.43 g, 2.28 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.57 g, 79%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 378.1 [M+H]+.
Step 4) 5-chloro-3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (0.22 g, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (0.13 g, 0.58 mmol), potassium carbonate (0.12 g, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (160 mg, 64%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 430.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.43 (br s, 1H), 7.55 (s, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.95 (s, 1H), 5.36 (s, 1H), 3.84 (s, 6H), 3.82 (d, J=4.7 Hz, 4H), 2.72 (t, J=7.2 Hz, 2H), 2.47-2.44 (m, 4H), 2.41 (t, J=7.5 Hz, 2H), 1.73-1.67 (m, 2H), 1.64-1.61 (m, 2H).
Example 4 3-(4-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-5-fluoro-1H-indole
Figure US09598401-20170321-C00036
Step 1) ethyl 4-(5-fluoro-1H-indol-3-yl)butanoate
The title compound was prepared by the procedure described in step 2 of example 1, using ethyl 6-oxohexanoate (1.0 g, 6.3 mmol) and 4-fluorophenylhydrazine hydrochloride (1.1 g, 6.8 mmol) in ethanol (125 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.94 g, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 250.2 [M+H]+.
Step 2) 4-(5-fluoro-1H-indol-3-yl)butan-1-ol
The title compound was prepared by the procedure described in step 3 of example 1, using ethyl 4-(5-fluoro-1H-indol-3-yl)butanoate (0.32 g, 1.27 mmol) and lithium aluminum hydride (0.19 g, 5.08 mmol) in THF (25 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (0.20 g, 76%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 208.2 [M+H]+.
Step 3) 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butan-1-ol (0.39 g, 1.9 mmol), TEA (0.3 mL, 2.28 mmol) and TsCl (0.43 g, 2.28 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.45 g, 65.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 362.2 [M+H]+.
Step 4) 3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-5-fluoro-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (168 mg, 70%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.01 (br s, 1H), 7.26-7.22 (m, 2H), 7.02 (d, J=1.6 Hz, 1H), 6.92 (td, J=9.1, 2.4 Hz, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.81 (t, J=4.9 Hz, 4H), 2.74 (t, J=7.4 Hz, 2H), 2.46 (t, J=5.1 Hz, 4H), 2.41 (t, J=7.6 Hz, 2H), 1.75-1.69 (m, 2H), 1.66-1.58 (m, 2H).
Example 5 3-(4-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00037
Step 1) 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile
To a mixture of aluminium chloride (9.0 g, 68.0 mmol) in DCM (90 mL) was added 4-chlorobutyryl chloride (9.6 g, 68.0 mmol) dropwise at 0° C. After the mixture was stirred at 0° C. for 30 mins, to it was added a mixture of 5-cyanoindole (8.1 g, 57.0 mmol) in DCM (800 mL) dropwise. The reaction mixture was heated to rt and stirred for 2 hours. Then the reaction mixture was poured into a mixture of ice water (50 g) in concentrated hydrochloric acid (50 mL), and stirred at rt for 20 hours. The resulting mixture was filtered, and the filter cake was washed with water (10 mL) and EtOAc (10 mL) in turn. Then the filter cake was dried to give the title compound as a yellow solid (8.9 g, 63%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 247.1 [M+H]+ and 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.63 (d, J=0.7 Hz, 1H), 8.35 (s, 1H), 7.62-7.60 (m, 1H), 7.52 (dd, J=8.4, 1.5 Hz, 1H), 3.69 (t, J=6.5 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.24-2.17 (m, 2H).
Step 2) 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile
To a mixture of 3-(4-chlorobutanoyl)-1H-indole-5-carbonitrile (0.49 g, 2.0 mmol) in isopropanol (20 mL) was added sodium borohydride (0.23 g, 6.0 mmol) in portions at 0° C. The reaction mixture was heated to 80° C. and stirred for 6 hours. Then the reaction mixture was cooled to 0° C. and quenched with saturated aqueous sodium carbonate solution (1 mL). The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (343 mg, 80%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 215.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.96 (d, J=0.8 Hz, 1H), 7.46-7.44 (m, 1H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 7.20 (s, 1H), 4.58 (s, 1H), 3.59 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.5 Hz, 2H), 1.79-1.73 (m, 2H), 1.65-1.60 (m, 2H).
Step 3) 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (0.41 g, 1.9 mmol), TEA (0.3 mL, 2.28 mmol) and TsCl (0.43 g, 2.28 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (0.56 g, 80.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 369.2 [M+H]+.
Step 4) 3-(4-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (163 mg, 67.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 421.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.34 (br s, 1H), 7.95 (s, 1H), 7.42-7.38 (m, 2H), 7.10 (s, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.81 (t, J=4.9 Hz, 4H), 2.78 (t, J=7.4 Hz, 2H), 2.48 (t, J=5.0 Hz, 4H), 2.43 (t, J=7.6 Hz, 2H), 1.75-1.72 (m, 2H), 1.64-1.62 (m, 2H).
Example 6 3-(3-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
Figure US09598401-20170321-C00038
Step 1) 3-(1H-indol-3-yl)propan-1-ol
To a solution of phenylhydrazine (2.25 g, 20.8 mmol) in a mixture of dilute sulphuric acid (4%, 50 mL) and N,N-dimethylacetamide (10 mL) was added 3,4-dihydro-2H-pyran (1.9 mL, 20.8 mmol) dropwise at 100° C. The reaction mixture was stirred at 100° C. for 20 hours. Then the reaction mixture was cooled to rt and extracted with EtOAc (50 mL×3). The combined organic phases were washed with water (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (2.29 g, 63%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 176.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.02 (br s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.09 (m, 1H), 6.95 (t, J=1.0 Hz, 1H), 3.71 (t, J=6.4 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.00-1.94 (m, 2H).
Step 2) 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(1H-indol-3-yl)propan-1-ol (0.88 g, 5.0 mmol), TEA (0.8 mL, 6.0 mmol) and TsCl (1.14 g, 6.0 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.04 g, 63%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 330.2 [M+H]+.
Step 3) 3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (191 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (155 mg, 70%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 382.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.99 (br s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 6.99 (s, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.82 (t, J=4.7 Hz, 4H), 2.81 (t, J=7.5 Hz, 2H), 2.50-2.46 (m, 6H), 1.98-1.92 (m, 2H).
Example 7 3-(3-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-5-methoxy-1H-indole
Figure US09598401-20170321-C00039
Step 1) 3-(5-methoxy-1H-indol-3-yl)propan-1-ol
The title compound was prepared by the procedure described in step 1 of example 6, using 4-methoxyphenylhydrazine hydrochloride (3.63 g, 20.8 mmol) and 3,4-dihydro-2H-pyran (1.9 mL, 20.8 mmol) in a mixture of dilute sulphuric acid (4%, 50 mL) and N,N-dimethylacetamide (10 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (1.5 g, 35%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 206.0 [M+H]+.
Step 2) 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(5-methoxy-1H-indol-3-yl)propan-1-ol (1.03 g, 5.0 mmol), TEA (0.8 mL, 6.0 mmol) and TsCl (1.14 g, 6.0 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.26 g, 70.%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 360.1 [M+H]+.
Step 3) 3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-5-methoxy-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (208 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (167 mg, 70.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 412.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.96 (br s, 1H), 7.26-7.24 (m, 1H), 7.03-7.01 (m, 2H), 6.86 (dd, J=8.7, 2.2 Hz, 1H), 5.39 (s, 1H), 3.95 (t, J=4.5 Hz, 4H), 3.87 (s, 3H), 3.85 (s, 6H), 2.79 (t, J=7.3 Hz, 2H), 2.67-2.61 (m, 6H), 2.09-2.05 (m, 2H).
Example 8 5-Chloro-3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
Figure US09598401-20170321-C00040
Step 1) 3-(5-chloro-1H-indol-3-yl)propan-1-ol
The title compound was prepared by the procedure described in step 1 of example 6, using 4-chlorophenylhydrazine hydrochloride (3.72 g, 20.8 mmol) and 3,4-dihydro-2H-pyran (1.9 mL, 20.8 mmol) in a mixture of dilute sulphuric acid (4%, 50 mL) and N,N-dimethylacetamide (10 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (2.35 g, 54%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 210.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.10 (br s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.26-7.24 (m, 2H), 7.11 (dd, J=8.6, 1.9 Hz, 1H), 6.99 (s, 1H), 3.71 (t, J=6.4 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 1.99-1.92 (m, 2H).
Step 2) 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(5-chloro-1H-indol-3-yl)propan-1-ol (1.05 g, 5.0 mmol), TEA (0.8 mL, 6.0 mmol) and TsCl (1.14 g, 6.0 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.09 g, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 364.1 [M+H]+.
Step 3) 5-chloro-3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (0.21 g, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (0.13 g, 0.58 mmol), potassium carbonate (0.12 g, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (159 mg, 66%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 416.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.05 (br s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.13 (dd, J=8.6, 1.8 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.83 (t, J=5.1 Hz, 4H), 2.76 (t, J=7.5 Hz, 2H), 2.48 (t, J=5.2 Hz, 4H), 2.45-2.43 (m, 2H), 1.96-1.89 (m, 2H).
Example 9 3-(3-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-5-fluoro-1H-indole
Figure US09598401-20170321-C00041
Step 1) 3-(5-fluoro-1H-indol-3-yl)propan-1-ol
The title compound was prepared by the procedure described in step 1 of example 6, using 4-fluorophenylhydrazine hydrochloride (3.38 g, 20.8 mmol) and 3,4-dihydro-2H-pyran (1.9 mL, 20.8 mmol) in a mixture of dilute sulphuric acid (4%, 50 mL) and N,N-dimethylacetamide (10 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (3.53 g, 88%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 194.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.05 (br s, 1H), 7.27-7.23 (m, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.96-6.91 (m, 1H), 3.72 (t, J=6.4 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.00-1.93 (m, 2H).
Step 2) 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propan-1-ol (0.97 g, 5.0 mmol), TEA (0.8 mL, 6.0 mmol) and TsCl (1.14 g, 6.0 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.28 g, 74%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 348.1 [M+H]+.
Step 3) 3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-5-fluoro-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (180 mg, 78%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 400.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.03 (br s, 1H), 7.25-7.24 (m, 2H), 7.03 (d, J=1.8 Hz, 1H), 6.93 (td, J=9.1, 2.4 Hz, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.82 (t, J=5.0 Hz, 4H), 2.76 (t, J=7.5 Hz, 2H), 2.50-2.44 (m, 6H), 1.95-1.77 (m, 2H).
Example 10 3-(3-(4-(4,6-Dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00042
Step 1) 3-(3-hydroxypropyl)-1H-indole-5-carbonitrile
The title compound was prepared by the procedure described in step 1 of example 6, using 4-cyanophenylhydrazine hydrochloride (3.53 g, 20.8 mmol) and 3,4-dihydro-2H-pyran (1.9 mL, 20.8 mmol) in a mixture of dilute sulphuric acid (4%, 50 mL) and N,N-dimethylacetamide (10 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (1.46 g, 35%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 201.1 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 11.36 (s, 1H), 7.50-7.48 (m, 1H), 7.38 (dd, J=8.4, 1.5 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.46 (t, J=5.1, 1H), 3.47-3.43 (m, 2H), 2.74 (d, J=7.6 Hz, 2H), 1.81-1.74 (m, 2H).
Step 2) 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate
The title compound was prepared by the procedure described in step 4 of example 1, using 3-(3-hydroxypropyl)-1H-indole-5-carbonitrile (1.00 g, 5.0 mmol), TEA (0.8 mL, 6.0 mmol) and TsCl (1.14 g, 6.0 mmol) in DCM (20 mL) to give the crude product, which was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.33 g, 75%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 355.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.51 (br s, 1H), 7.83 (s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.40 (s, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.08 (d, J=2.2 Hz, 1H), 4.08 (t, J=6.1 Hz, 2H), 2.81 (t, J=7.3 Hz, 2H), 2.45 (s, 3H), 2.06-1.99 (m, 2H).
Step 3) 3-(3-(4-(4,6-dimethoxypyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4,6-dimethoxy-2-(piperazin-1-yl)pyrimidine (130 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (155 mg, 66%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 407.5 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.33 (br s, 1H), 7.98 (s, 1H), 7.41-7.38 (m, 2H), 7.12 (s, 1H), 5.36 (s, 1H), 3.85 (s, 6H), 3.83 (t, J=5.0 Hz, 4H), 2.81 (t, J=7.5 Hz, 2H), 2.48 (t, J=4.9 Hz, 4H), 2.45-2.44 (m, 2H), 1.96-1.92 (m, 2H).
Example 11 3-(4-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
Figure US09598401-20170321-C00043
Step 1) 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4,6-dimethylpyrimidine (1.03 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.80 g, 58%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 193.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 6.26 (s, 1H), 3.80 (t, J=5.1 Hz, 4H), 2.92 (t, J=5.1 Hz, 4H), 2.28 (s, 6H).
Step 2) 3-(4-(4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(1H-indol-3-yl)butyl 4-methylbenzenesulfonate (200 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (126 mg, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 364.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.97 (br s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 7.12-7.09 (m, 1H), 6.98 (d, J=1.7 Hz, 1H), 6.26 (s, 1H), 3.84 (t, J=4.9 Hz, 4H), 2.79 (d, J=7.4 Hz, 2H), 2.49 (t, J=5.0 Hz, 4H), 2.42 (t, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.79-1.72 (m, 2H), 1.68-1.62 (m, 2H).
Example 12 3-(4-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-5-methoxy-1H-indole
Figure US09598401-20170321-C00044
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-methoxy-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (216 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (114 mg, 50%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 394.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.92 (br s, 1H), 7.26-7.22 (m, 1H), 7.03 (d, J=1.8 Hz, 1H), 6.96 (s, 1H), 6.86 (dd, J=8.7, 2.1 Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H), 3.84 (d, J=4.6 Hz, 4H), 2.79 (s, 6H), 2.75 (t, J=7.2 Hz, 2H), 2.49 (t, J=4.7 Hz, 4H), 2.43 (t, J=7.5 Hz, 2H), 1.76-1.68 (m, 2H), 1.66-1.63 (m, 2H).
Example 13 5-Chloro-3-(4-(4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
Figure US09598401-20170321-C00045
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-chloro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (219 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 63%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 398.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.99 (br s, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.27-7.25 (m, 1H), 7.13 (dd, J=8.6, 2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.26 (s, 1H), 3.84 (t, J=5.0 Hz, 4H), 2.74 (t, J=7.3 Hz, 2H), 2.49 (t, J=5.1 Hz, 4H), 2.42 (t, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.73-1.71 (m, 2H), 1.65-1.60 (m, 2H).
Example 14 3-(4-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-5-fluoro-1H-indole
Figure US09598401-20170321-C00046
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (177 mg, 80.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 382.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.96 (br s, 1H), 7.25-7.22 (m, 2H), 7.02 (s, 1H), 6.92 (d, J=9.0, 2.4 Hz, 1H), 6.26 (s, 1H), 3.83 (t, J=4.8 Hz, 4H), 2.74 (t, J=7.3 Hz, 2H), 2.48 (t, J=5.0 Hz, 4H), 2.41 (t, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.77-1.71 (m, 2H), 1.65-1.59 (m, 2H).
Example 15 3-(4-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00047
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (148 mg, 66%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 389.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.31 (br s, 1H), 7.95 (s, 1H), 7.43-7.37 (m, 2H), 7.10 (s, 1H), 6.26 (s, 1H), 3.83 (t, J=4.9 Hz, 4H), 2.79-2.77 (m, 2H), 2.48 (t, J=5.0 Hz, 4H), 2.42-2.39 (m, 2H), 2.28 (s, 6H), 1.76-1.72 (m, 2H), 1.66-1.63 (m, 2H).
Example 16 3-(3-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
Figure US09598401-20170321-C00048
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (191 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (167 mg, 82%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.98 (br s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.26 (s, 1H), 3.85 (t, J=4.9 Hz, 4H), 2.81 (t, J=7.6 Hz, 2H), 2.52-2.47 (m, 6H), 2.28 (s, 6H), 1.99-1.93 (m, 2H).
Example 17 3-(3-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)propyl)-5-methoxy-1H-indole
Figure US09598401-20170321-C00049
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-methoxy-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (208 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (132 mg, 60.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 380.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.03 (br s, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.26 (s, 1H), 3.86 (s, 3H), 3.83 (t, J=4.9 Hz, 4H), 2.76 (t, J=6.8 Hz, 2H), 2.51 (t, J=5.1 Hz, 4H), 2.46 (d, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.97-1.90 (m, 2H).
Example 18 5-Chloro-3-(3-(4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
Figure US09598401-20170321-C00050
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-chloro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (211 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (144 mg, 65%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 384.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.01 (br s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.27-7.25 (m, 1H), 7.13 (dd, J=8.6, 2.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.26 (s, 1H), 3.86 (t, J=5.0 Hz, 4H), 2.76 (d, J=7.5 Hz, 2H), 2.50 (t, J=5.1 Hz, 4H), 2.46 (d, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.97-1.90 (m, 2H).
Example 19 3-(3-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)propyl)-5-fluoro-1H-indole
Figure US09598401-20170321-C00051
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (170 mg, 80%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 368.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.00 (br s, 1H), 7.26-7.24 (m, 2H), 7.04 (d, J=1.7 Hz, 1H), 6.93 (td, J=9.1, 2.4 Hz, 1H), 6.26 (s, 1H), 3.85 (t, J=4.9 Hz, 4H), 2.75 (t, J=7.5 Hz, 2H), 2.50 (t, J=5.1 Hz, 4H), 2.46 (t, J=7.7 Hz, 2H), 2.28 (s, 6H), 1.95-1.90 (m, 2H).
Example 20 3-(3-(4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00052
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4,6-dimethyl-2-(piperazin-1-yl)pyrimidine (112 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (152 mg, 70.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 375.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.32 (br s, 1H), 7.98 (s, 1H), 7.43-7.38 (m, 2H), 7.12 (d, J=2.0 Hz, 1H), 6.27 (s, 1H), 3.86 (t, J=4.9 Hz, 4H), 2.81 (t, J=7.5 Hz, 2H), 2.51 (t, J=5.0 Hz, 4H), 2.46 (t, J=7.6 Hz, 2H), 2.28 (s, 6H), 1.99-1.91 (m, 2H).
Example 21 3-(4-(4-(4-Methoxy-6-methylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00053
Step 1) 4-methoxy-6-methyl-2-(piperazin-1-yl)pyrimidine
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-methoxy-6-methylpyrimidine (1.14 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.75 g, 50.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 209.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 5.84 (s, 1H), 3.85 (s, 3H), 3.79 (t, J=5.1 Hz, 4H), 2.92 (t, J=5.1 Hz, 4H), 2.46 (s, 3H).
Step 2) 3-(4-(4-(4-methoxy-6-methylpyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methoxy-6-methyl-2-(piperazin-1-yl)pyrimidine (121 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (147 mg, 63%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 405.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.34 (br s, 1H), 7.95 (s, 1H), 7.40 (t, J=7.2 Hz, 2H), 7.11 (t, J=10.6 Hz, 1H), 5.85 (s, 1H), 3.86 (s, 3H), 3.84 (m, 4H), 2.79 (t, J=7.3 Hz, 2H), 2.52 (t, J=4.9 Hz, 4H), 2.46 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 1.76-1.71 (m, 2H), 1.68-1.65 (m, 2H).
Example 22 3-(3-(4-(4-Methoxy-6-methylpyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00054
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methoxy-6-methyl-2-(piperazin-1-yl)pyrimidine (121 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (130 mg, 57%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 391.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.35 (br s, 1H), 7.96 (s, 1H), 7.41-7.38 (m, 2H), 7.16 (s, 1H), 5.85 (s, 1H), 4.09-4.07 (m, 4H), 3.86 (s, 3H), 2.81 (t, J=7.4 Hz, 2H), 2.56-2.50 (m, 4H), 2.25 (s, 3H), 2.04-1.97 (m, 2H), 1.28-1.24 (m, 2H).
Example 23 2-(4-(4-(5-Fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)pyrimidine-4-carbonitrile
Figure US09598401-20170321-C00055
Step 1) 2-(piperazin-1-yl)pyrimidine-4-carbonitrile
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-cyanopyrimidine (1.00 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (0.81 g, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 190.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.43 (d, J=4.6 Hz, 1H), 6.72 (d, J=4.6 Hz, 1H), 3.81 (t, J=5.1 Hz, 4H), 2.92 (t, J=5.1 Hz, 4H).
Step 2) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)pyrimidine-4-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (186 mg, 85%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 379.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.45 (d, J=4.7 Hz, 1H), 7.97 (s, 1H), 7.30-7.28 (m, 2H), 7.05 (d, J=1.0 Hz, 1H), 6.95 (d, J=9.0, 2.5 Hz, 1H), 6.75 (d, J=4.7 Hz, 1H), 3.82-3.80 (m, 4H), 2.68 (t, J=7.3 Hz, 2H), 2.56-2.49 (m, 4H), 2.38-2.35 (t, J=7.2 Hz, 2H), 1.83-1.75 (m, 2H).
Example 24 3-(4-(4-(4-Cyanopyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00056
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (156 mg, 70%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 386.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.42 (d, J=4.7 Hz, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.43-7.38 (m, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.73 (d, J=4.6 Hz, 1H), 6.75 (d, J=4.7 Hz, 1H), 3.87 (t, J=4.6 Hz, 4H), 2.79 (t, J=7.3 Hz, 2H), 2.52 (t, J=4.6 Hz, 4H), 2.46 (t, J=7.5 Hz, 2H), 1.75-1.70 (m, 2H), 1.68-1.60 (m, 2H).
Example 25 2-(4-(3-(5-Fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)pyrimidine-4-carbonitrile
Figure US09598401-20170321-C00057
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 69%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 365.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.42 (d, J=4.6 Hz, 1H), 7.99 (s, 1H), 7.28-7.23 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.73 (d, J=4.7 Hz, 1H), 3.89 (t, J=4.9 Hz, 4H), 2.77 (t, J=7.5 Hz, 2H), 2.53 (t, J=5.0 Hz, 4H), 2.49 (t, J=7.6 Hz, 2H), 1.95-1.87 (m, 2H).
Example 26 3-(3-(4-(4-Cyanopyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00058
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carbonitrile (110 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (130 mg, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 372.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.43 (d, J=4.7 Hz, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.42-7.41 (m, 2H), 7.16 (s, 1H), 6.74 (d, J=4.6 Hz, 1H), 3.93-3.91 (m, 4H), 2.82 (t, J=7.4 Hz, 2H), 2.57-2.52 (m, 6H), 2.04-1.99 (m, 2H).
Example 27 2-(4-(4-(5-Fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00059
Step 1) 2-(piperazin-1-yl)pyrimidine-4-carboxamide
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloropyrimidine-4-carboxamide (1.13 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.04 g, 70.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 208.1 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 8.55 (d, J=4.8 Hz, 1H), 8.18 (s, 1H), 7.72 (s, 1H), 7.10 (d, J=4.8 Hz, 1H), 3.82 (t, J=4.9 Hz, 4H), 2.84 (t, J=5.1 Hz, 4H).
Step 2) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)pyrimidine-4-carboxamide
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (180 mg, 78%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 397.3 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 10.83 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 7.70-7.68 (m, 1H), 7.33-7.29 (m, 1H), 7.25 (dd, J=10.1, 2.5 Hz, 1H), 7.18 (d, J=2.2 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 6.88 (dd, J=9.2, 2.5 Hz, 1H), 3.79 (m, 4H), 2.67 (t, J=7.3 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H), 2.41-2.37 (m, 4H), 1.67-1.61 (m, 2H), 1.56-1.49 (m, 2H).
Example 28 2-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00060
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (145 mg, 62%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 404.3 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 11.35 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.70 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.4, 1H), 7.33 (s, 1H), 7.08 (d, J=4.8 Hz, 1H), 3.79-3.78 (m, 4H), 2.74 (t, J=7.4 Hz, 2H), 2.39 (t, J=4.8 Hz, 4H), 2.35 (t, J=7.5 Hz, 2H), 1.69-1.65 (m, 2H), 1.54-1.51 (m, 2H).
Example 29 2-(4-(3-(5-Fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00061
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (188 mg, 85%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 383.1 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 10.84 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.33-7.30 (m, 1H), 7.25 (dd, J=10.1, 2.5 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 6.88 (dd, J=9.2, 2.5 Hz, 1H), 3.82-3.79 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 2.42-2.39 (m, 4H), 2.37 (t, J=7.2 Hz, 2H), 1.78-1.68 (m, 2H).
Example 30 2-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00062
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)pyrimidine-4-carboxamide (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.1 mol) in acetonitrile (15 mL) to give the title compound as a white solid (157 mg, 70%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 390.1 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 11.37 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.4, 1.4 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 3.82 (t, J=4.7 Hz, 4H), 2.75 (t, J=7.4 Hz, 2H), 2.41 (t, J=4.7 Hz, 4H), 2.36 (t, J=7.2 Hz, 2H), 1.87-1.80 (m, 2H).
Example 31 5-Fluoro-3-(4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
Figure US09598401-20170321-C00063
Step 1) 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-4-(trifluoromethyl)pyrimidine (1.31 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as yellow oil (1.25 g, 75%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 233.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.48 (d, J=4.8 Hz, 1H), 6.73 (d, J=4.8 Hz, 1H), 3.84 (t, J=5.1 Hz, 4H), 2.93 (t, J=5.1 Hz, 4H).
Step 2) 5-fluoro-3-(4-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 81.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 422.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 7.97-7.95 (m, 1H), 7.25-7.21 (m, 2H), 7.03 (d, J=1.9 Hz, 1H), 6.92 (td, J=9.1, 2.5 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 3.91 (t, J=4.7 Hz, 4H), 2.74 (t, J=7.3 Hz, 2H), 2.54 (t, J=4.7 Hz, 4H), 2.46 (t, J=7.5 Hz, 2H), 1.77-1.61 (m, 4H).
Example 32 3-(4-(4-(4-(Trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00064
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (132 mg, 53%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 429.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz), δ (ppm): 8.47 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 7.95 (s, 1H), 7.41-7.40 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 6.75 (d, J=4.8 Hz, 1H), 3.92 (t, J=4.6 Hz, 4H), 2.79 (t, J=7.3 Hz, 2H), 2.56 (t, J=4.7 Hz, 4H), 2.48 (t, J=7.5 Hz, 2H), 1.79-1.66 (m, 4H).
Example 33 5-Fluoro-3-(3-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole
Figure US09598401-20170321-C00065
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (208 mg, 88.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 408.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.28-7.23 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.93 (td, J=9.0, 2.5 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 3.92 (t, J=5.0 Hz, 4H), 2.77 (t, J=7.5 Hz, 2H), 2.55 (t, J=5.0 Hz, 4H), 2.50 (t, J=7.6 Hz, 2H), 1.99-1.92 (m, 2H).
Example 34 3-(3-(4-(4-(Trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00066
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine (135 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (146 mg, 61%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 415.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (d, J=4.8 Hz, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.41-7.37 (m, 2H), 7.14 (d, J=2.1 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 3.92 (t, J=4.9 Hz, 4H), 2.82 (t, J=7.4 Hz, 2H), 2.55 (t, J=5.0 Hz, 4H), 2.50 (t, J=7.5 Hz, 2H), 1.98-1.93 (m, 2H).
Example 35 3-(4-(4-(5-Fluoropyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00067
Step 1) 5-fluoro-2-(piperazin-1-yl)pyrimidine
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloro-5-fluoropyrimidine (0.95 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a white solid (0.72 g, 55%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 183.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.19 (s, 2H), 3.74 (t, J=5.1 Hz, 4H), 2.93 (t, J=5.1 Hz, 4H).
Step 2) 3-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 5-fluoro-2-(piperazin-1-yl)pyrimidine (106 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (131 mg, 60%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 379.3 [M+H]+ and 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.26 (d, J=0.5 Hz, 2H), 7.98 (s, 1H), 7.45 (dd, J=8.4, 0.4 Hz, 1H), 7.35 (dd, J=8.4, 1.5 Hz, 1H), 7.21 (s, 1H), 3.75 (t, J=5.1 Hz, 4H), 2.82 (t, J=7.3 Hz, 2H), 2.50 (t, J=5.1 Hz, 4H), 2.44 (t, J=7.7 Hz, 2H), 1.79-1.71 (m, 2H), 1.67-1.59 (m, 2H).
Example 36 3-(3-(4-(5-Fluoropyrimidin-2-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure US09598401-20170321-C00068
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 5-fluoro-2-(piperazin-1-yl)pyrimidine (106 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (135 mg, 64%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 365.3 [M+H]+ and 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.14 (m, 2H), 7.90 (s, 1H), 7.39-7.37 (m, 1H), 7.31 (dd, J=8.4, 1.5 Hz, 1H), 7.10 (s, 1H), 3.73 (d, J=5.1 Hz, 4H), 2.75 (d, J=7.4 Hz, 2H), 2.50 (t, J=5.1 Hz, 4H), 2.46-2.43 (m, 2H), 1.95-1.87 (m, 2H).
Example 37 Ethyl 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
Figure US09598401-20170321-C00069
Step 1) ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate
The title compound was prepared by the procedure described in step 5 of example 1, using ethyl 2-bromo-4-methylthiazole-5-carboxylate (1.80 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.65 g, 90%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 256.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 4.25 (q, J=7.2 Hz, 2H), 3.52-3.49 (m, 4H), 2.97-2.94 (m, 4H), 2.54 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).
Step 2) ethyl 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (211 mg, 82%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 445.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.19 (br s, 1H), 7.23-7.28 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.93 (td, J=8.8, 2.4 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.54-3.57 (m, 4H), 2.75 (t, J=7.2 Hz, 2H), 2.57 (s, 3H), 2.54-2.51 (m, 4H), 2.45-2.42 (m, 2H), 1.76-1.71 (m, 2H), 1.65-1.59 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).
Example 38 Ethyl 2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
Figure US09598401-20170321-C00070
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (200 mg, 80%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 431.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.98 (br s, 1H), 7.25-7.22 (m, 2H), 7.02 (d, J=1.6 Hz, 1H), 6.93 (td, J=8.8, 2.4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.57-3.54 (m, 4H), 2.76 (t, J=7.2 Hz, 2H), 2.55-2.52 (m, 7H), 2.48-2.44 (m, 2H), 1.94-1.86 (m, 2H), 1.32 (t, J=7.2 Hz, 3H).
Example 39 Ethyl 2-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
Figure US09598401-20170321-C00071
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (196 mg, 75%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 452.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (br s, 1H), 7.94 (s, 1H), 7.40-7.36 (m, 2H), 7.09 (d, J=2.0 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.55-3.52 (m, 4H), 2.77 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.52-2.50 (m, 4H), 2.44-2.40 (m, 2H), 1.74-1.70 (m, 2H), 1.63-1.57 (m, 2H), 1.32 (t, J=7.2 Hz, 3H).
Example 40 Ethyl 2-(4-(3-(5-cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carboxylate
Figure US09598401-20170321-C00072
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (205 mg, 0.58 mmol), ethyl 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxylate (148 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (195 mg, 77%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 438.3 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.40 (br s, 1H), 7.90 (s, 1H), 7.34-7.32 (m, 2H), 7.04 (d, J=1.6 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.50-3.48 (m, 4H), 2.73 (t, J=7.2 Hz, 2H), 2.47 (s, 3H), 2.46-2.45 (m, 4H), 2.40-2.36 (m, 2H), 1.88-1.80 (m, 2H), 1.25 (t, 3H, J=7.2 Hz).
Example 41 2-(4-(4-(5-Fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxamide
Figure US09598401-20170321-C00073
Step 1) 2-bromo-4-methylthiazole-5-carboxamide
A mixture of ethyl 2-bromo-4-methylthiazole-5-carboxylate (6.0 g, 23.99 mmol) in concentrated ammonia (175 mL) was stirred at rt for 20 hours. Then the reaction mixture was filtered. The filter cake was washed with water and dried to give the title compound as a red solid (3.03 g, 57%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 223.0 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 5.79 (br s, 2H), 2.71 (s, 3H).
Step 2) 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide
The title compound was prepared by the procedure described in step 5 of example 1, using 2-bromo-4-methylthiazole-5-carboxamide (1.60 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.59 g, 98%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 227.0 [M+H]+.
Step 3) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxamide
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (210 mg, 87%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 416.1 [M+H]+ and 1H NMR (CDCl3/CD3OD=1/1, 400 MHz) δ (ppm): 7.25 (dd, J=8.8, 4.4 Hz, 1H), 7.15 (dd, J=9.6, 2.4 Hz, 1H), 7.03 (s, 1H), 6.83 (td, J=8.8, 2.4 Hz, 1H), 3.51-3.49 (m, 4H), 2.73 (t, J=7.2 Hz, 2H), 2.55-2.53 (m, 4H), 2.47 (s, 3H), 2.45-2.41 (m, 2H), 1.74-1.70 (m, 2H), 1.62-1.57 (m, 2H).
Example 42 2-(4-(3-(5-Fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carboxamide
Figure US09598401-20170321-C00074
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 85%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 402.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.07 (br s, 1H), 7.24-7.22 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.93 (td, J=8.8, 2.0 Hz, 1H), 5.50 (br s, 2H), 3.55-3.52 (m, 4H), 2.75 (t, J=7.2 Hz, 2H), 2.55-2.51 (m, 7H), 2.47-2.44 (m, 2H), 1.92-1.86 (m, 2H).
Example 43 2-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carboxamide
Figure US09598401-20170321-C00075
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (198 mg, 81%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 423.1 [M+H]+ and 1H NMR (CDCl3/CD3OD=1/1, 400 MHz) δ (ppm): 7.90 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.31 (dd, J=8.4, 0.8 Hz, 1H), 7.12 (s, 1H), 3.50-3.48 (m, 4H), 2.77 (t, J=7.2 Hz, 2H), 2.55-2.52 (m, 4H), 2.47-2.41 (m, 5H), 1.74-1.70 (m, 2H), 1.62-1.59 (m, 2H).
Example 44 2-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carboxamide
Figure US09598401-20170321-C00076
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (131 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (139 mg, 59%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 409.3 [M+H]+ and 1H NMR (CDCl3/CD3OD=1/1, 400 MHz) δ (ppm): 7.94 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.11 (dd, J=8.4, 1.2 Hz, 1H), 3.54-3.52 (m, 4H), 2.80 (t, J=7.2 Hz, 2H), 2.58-2.56 (m, 4H), 2.50-2.47 (m, 5H), 1.97-1.89 (m, 2H).
Example 45 2-(4-(4-(5-Fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carbonitrile
Figure US09598401-20170321-C00077
Step 1) 2-bromo-4-methylthiazole-5-carbonitrile
To a mixture of 2-bromo-4-methylthiazole-5-carboxamide (1.02 g, 4.60 mmol) in DCM (40 mL) was added TEA (1.6 mL, 11.50 mmol) at 0° C., and then added trifluoroacetic anhydride (1.2 mL) dropwise. After the reaction mixture was stirred at 0° C. for 0.5 hour, it was further stirred at rt for 3 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (120 mL) and extracted with DCM (90 mL×2). The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated in vacuo. and then dried to give the title compound as a red solid (0.88 g, 94%). The compound was characterized by the following spectroscopic data: GC-MS: 203.9 M+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 2.61 (s, 3H).
Step 2) 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile
The title compound was prepared by the procedure described in step 5 of example 1, using 2-bromo-4-methylthiazole-5-carbonitrile (1.46 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and anhydrous piperazine (1.24 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.47 g, 98.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 209.0 [M+H]+ and 1H NMR (CD3Cl, 400 MHz) δ (ppm): 3.51-3.49 (m, 4H), 2.97-2.95 (m, 4H), 2.38 (s, 3H).
Step 3) 2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carbonitrile
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-fluoro-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (210 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (194 mg, 84%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 398.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.01 (br s, 1H), 7.30-7.23 (m, 2H), 7.04 (d, J=2.0 Hz, 1H), 6.95 (td, J=8.8, 2.4 Hz, 1H), 3.57-3.54 (m, 4H), 2.76 (t, J=7.2 Hz, 2H), 2.56-2.53 (m, 4H), 2.47-2.43 (m, 2H), 2.40 (s, 3H), 1.77-1.72 (m, 2H), 1.63-1.59 (m, 2H).
Example 46 2-(4-(3-(5-Fluoro-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carbonitrile
Figure US09598401-20170321-C00078
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (201 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (188 mg, 85%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 384.2 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.10 (br s, 1H), 7.25-7.24 (m, 2H), 7.04 (d, J=2.0 Hz, 1H), 6.95 (td, J=8.8, 2.4 Hz, 1H), 3.59-3.56 (m, 4H), 2.78 (t, J=7.2 Hz, 2H), 2.57-2.55 (m, 4H), 2.50-2.47 (m, 2H), 2.41 (s, 3H), 1.96-1.90 (m, 2H).
Example 47 2-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-4-methylthiazole-5-carbonitrile
Figure US09598401-20170321-C00079
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (182 mg, 78%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 405.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.41 (br s, 1H), 7.94 (s, 1H), 7.40-7.36 (m, 2H), 7.10-7.08 (m, 1H), 3.56-3.53 (m, 4H), 2.78 (t, J=7.2 Hz, 2H), 2.55-2.52 (m, 4H), 2.46-2.43 (m, 2H), 2.38 (s, 3H), 1.76-1.70 (m, 2H), 1.62-1.58 (m, 2H).
Example 48 2-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-4-methylthiazole-5-carbonitrile
Figure US09598401-20170321-C00080
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 4-methyl-2-(piperazin-1-yl)thiazole-5-carbonitrile (120 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (181 mg, 80%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 391.1 [M+H]+ and 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.49 (br s, 1H), 7.96 (s, 1H), 7.40-7.38 (m, 2H), 7.11-7.10 (m, 1H), 3.58-3.55 (m, 4H), 2.80 (t, J=7.2 Hz, 2H), 2.56-2.53 (m, 4H), 2.48-2.44 (m, 2H), 2.38 (s, 3H), 1.95-1.87 (m, 2H).
Example 49 2-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)-3-methylpiperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00081
Step 1) 2-(3-methylpiperazin-1-yl)pyrimidine-4-carboxamide
The title compound was prepared by the procedure described in step 5 of example 1, using 2-chloropyrimidine-4-carboxamide (1.13 g, 7.2 mmol), potassium carbonate (1.00 g, 7.2 mmol) and 2-methylpiperazine (1.44 g, 14.4 mmol) in DMF (10 mL) to give the title compound as a yellow solid (1.03 g, 65.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 222.2 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 8.52 (d, J=4.6 Hz, 1H), 8.17 (br s, 1H), 7.75 (br s, 1H), 7.07 (d, J=4.6 Hz, 1H), 4.62 (s, 2H), 2.92 (d, J=11.7 Hz, 1H), 2.80 (td, J=11.8 Hz, 5.9 Hz, 1H), 2.62 (dd, J=11.5, 9.4 Hz, 2H), 2.43 (t, J=11.4 Hz, 1H), 1.02 (d, J=6.1 Hz, 3H).
Step 2) 2-(4-(3-(5-cyano-1H-indol-3-yl)propyl)-3-methylpiperazin-1-yl)pyrimidine-4-carboxamide
The title compound was prepared by the procedure described in step 6 of example 1, using 3-(5-cyano-1H-indol-3-yl)propyl 4-methylbenzenesulfonate (206 mg, 0.58 mmol), 2-(3-methylpiperazin-1-yl)pyrimidine-4-carboxamide (128 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (163 mg, 70.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 404.3 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 11.38 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.40 (dd, J=8.4, 1.2 Hz, 1H), 7.36 (d, J=1.1 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 4.32 (d, J=1.6 Hz, 2H), 3.32-3.28 (m, 1H), 3.04-2.97 (m, 1H), 2.86 (d, J=9.8 Hz, 1H), 2.79-2.70 (m, 3H), 2.41-2.37 (m, 1H), 2.31-2.27 (m, 1H), 2.24-2.20 (m, 1H), 1.85-1.77 (m, 2H), 1.00 (d, J=5.9 Hz, 3H).
Example 50 2-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)-3-methylpiperazin-1-yl)pyrimidine-4-carboxamide
Figure US09598401-20170321-C00082
The title compound was prepared by the procedure described in step 6 of example 1, using 4-(5-cyano-1H-indol-3-yl)butyl 4-methylbenzenesulfonate (214 mg, 0.58 mmol), 2-(3-methylpiperazin-1-yl)pyrimidine-4-carboxamide (128 mg, 0.58 mmol), potassium carbonate (120 mg, 0.87 mmol) and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (15 mL) to give the title compound as a white solid (164 mg, 68.0%). The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 418.3 [M+H]+ and 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 11.37 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.74 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.40 (dd, J=8.4, 1.2 Hz, 1H), 7.34 (d, J=1.2 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 4.32 (d, J=7.5 Hz, 2H), 3.27 (t, J=10.3 Hz, 1H), 2.97 (dd, J=12.2, 9.3 Hz, 1H), 2.83-2.79 (m, 1H), 2.76-2.72 (m, 3H), 2.37-2.33 (m, 1H), 2.25-2.20 (m, 1H), 2.16 (t, J=9.4 Hz, 1H), 1.70-1.60 (m, 2H), 1.52-1.47 (m, 2H), 1.03 (d, J=6.1 Hz, 3H).
BIOLOGICAL TEST Example A: Evaluation of the Inhibitory Effect on [3H]5-HT Uptake in Rat Synaptosome Test Method
The synaptosomes (150 μg) prepared from the rat brain were incubated at 37° C. for 15 minutes with 0.1 μCi [3H]5-HT in the absence or presence of the test compound or the reference compound in a buffer solution containing 106.2 mM NaCl, 4.5 mM KCl, 2.25 mM MgSO4, 1.08 mM NaH2PO4, 22.5 mM NaHCO3, 9.9 mM glucose, 9 μM EGTA and 45 μM ascorbic acid (pH 7.4).
The basal control activity was determined by incubating the same mixture at 4° C. for 15 minutes in the presence of 10 μM imipramine to block the uptake of 5-HT, which was taken as the standard reference compound and tested in each experiment at several concentrations to obtain an inhibition curve.
Following the incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed twice with an ice-cold incubation buffer using a 96-sample cell harvester (Unifilter, Packard) to eliminate free [3H]5-HT. The filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The experimental results were expressed as a percent inhibition of the control uptake of [3H]5-HT.
Data Analysis
Inhibition of serotonin transporter in rat synaptosome was measured by the concentrations of [3H]5-HT. The test compounds were required to be tested at least twice in the case of the concentration thereof being greater than 6 log, and the obtained data were subjected to a nonlinear regression analysis via a curve of Hill equation, to obtain IC50 value. The experimental results of the compounds provided herein inhibiting [3H]5-HT uptake in rat synaptosome were showed in Table 1.
TABLE 1
Inhibitory effect of the compounds provided
herein on [3H]5-HT uptake in rat synaptosome
Example No. IC50 (nM)
4 6.4
5 11
6 24
8 81
9 4.4
10 3.6
11 82
14 12
15 6.9
16 53
18 31
19 7.9
20 2.0
21 2.6
22 2.7
23 6.1
24 1.9
25 4.5
26 2.6
27 2.7
28 1.0
29 1.4
30 0.75
31 16
32 10
33 11
34 5.9
35 4.7
36 8.2
37 7.0
38 11
39 2.9
40 3.5
41 2.4
42 5.3
43 0.85
44 4.3
45 8.3
46 18
47 1.5
48 7.7
49 0.28
50 0.36
The experimental results indicated that the compounds provided herein exhibited potent inhibitory activity on 5-HT reuptake.
Example B: Evaluation of the Affinity for Human 5-HT1A Receptor Test Method
Human HEK-293 cell homogenates (36 μg protein) were incubated at 22° C. for 60 minutes with 0.3 nM [3H]8-OH-DPAT (Perkin-Elmer) in the absence or presence of the test compound in a buffer solution containing 50 mM Tris-HCl (pH 7.4), 10 mM MgSO4, 0.5 mM EDTA, 2 μg/ml aprotinine.
The non-specific binding value was determined by incubating the same mixture in the presence of 10 μM 8-OH-DPAT, which was used as the standard reference compound and tested in each experiment at several concentrations to obtain a competition curve.
Following the incubation, the samples were filtered rapidly under vacuum through glass fiber filter (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The experimental results were expressed as a percent inhibition of the control radioligand specific binding, and Ki was the inhibition constant.
Data Analysis
Binding assay of [3H] 8-OH-DPAT (0.3 nM) with 5-HT1A, receptor in human HEK-293 cell was tested by scintillation proximity assay of membrane. The test compounds were required to be tested at least three times in the case of the concentration thereof being greater than 6 log, and the obtained data were subjected to a nonlinear regression analysis via a curve of Hill equation, to obtain IC50 value, and then calculated by ChengPrusoff equation to obtain Ki value. The experimental results of the binding affinity of the compounds provided herein for 5-HT1A receptor were showed in Table 2.
TABLE 2
Binding affinity of the compounds
provided herein for 5-HT1A receptor
Example No. Ki (nM)
1 3.3
2 1.4
3 1.1
4 2.8
5 2.3
6 4.8
7 0.19
8 2.0
9 3.4
10 1.3
11 1.1
12 1.1
13 1.8
14 1.7
15 2.9
16 4.1
17 0.29
18 0.71
19 1.4
20 1.1
21 0.65
22 1.5
23 18
24 6.2
25 4.0
26 8.0
27 60
28 10
29 12
30 14
31 2.0
32 0.7
33 1.0
34 0.2
37 5.5
38 0.27
39 0.79
40 0.3
41 23
42 4.5
43 12
44 3.7
45 14
46 4.2
47 5.0
48 2.6
The experimental results indicated that the compounds disclosed herein exhibited high binding affinity for 5-HT1A receptor.
Example C: Evaluation of the Affinity for Human Dopamine D2S Receptor Test Method
Cell membrane homogenates (24 μg protein) were incubated at 22° C. for 60 minutes with 0.3 nM [3H]methyl-spiperone in the absence or presence of the test compound in a buffer solution containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl2 and 1 mM EDTA.
The non-specific binding value was determined by incubating the same mixture in the presence of 10 μM (+)butaclamol.
Following the incubation, the samples were filtered rapidly under vacuum through glass fiber filter (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and the retained radioactivity was measured in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
Data Analysis
The experimental results were expressed as a percent inhibition of the control radioligand specific binding, and Ki was the inhibition constant. The standard reference compound was (+)butaclamol, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 was calculated, and then Ki value was calculated by ChengPrusoff equation. The experimental results of the binding affinity of the compounds provided herein for D2S receptor were showed in Table 3.
TABLE 3
Binding affinity of the compounds provided herein for D2S receptor
Example No. Ki (nM)
4 110
10 200
16 110
26 190
27 >1000
28 310
29 230
30 >1000
37 130
38 270
40 >1000
41 140
42 310
44 >1000
45 >1000
46 >1000
47 130
The experimental results indicated that the compounds disclosed herein exhibited good selectivity for D2S receptor
Example D: Pharmacokinetic Evaluation
In vivo pharmacokinetic studies of the compounds disclosed herein in rats, dogs and monkeys were assessed. The compounds disclosed herein were administered in the form of a saline solution containing 5% DMSO, 5% Kolliphor HS 15, 2% (2% HCl) and 88% Saline, or the solution containing 10% DMSO, 10% Kolliphor HS 15 and 80% physiological saline. For intravenous administration, the animals were administered with a dose of 1 mg/kg, and 0.3 mL of blood was collected at the time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after drug administration (the time point of drug administration was set as 0 h). For oral (p.o.) administration, the animals were administered with a dose of 5 mg/kg, and 0.3 mL of blood was collected at the time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after drug administration (the time point of drug administration was set as 0 h). All the blood samples were processed to separate plasma by centrifugation at 3000 rpm or 4000 rpm for 10 minutes. The plasma was collected and stored at −20° C. or −70° C. until LC/MS/MS analysis.
The experimental results indicated that the compounds disclosed herein exhibited good pharmacokinetic properties in rats, dogs and monkeys.
Reference throughout this specification to “one embodiment”, “an embodiment”, “some embodiments”, “explanatory embodiment”, “an example”, “a specific example” or “some examples”, means that a particular feature, structure, material or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments”, “in one embodiment”, “in an embodiment”, “in another example”, “in an example”, “in a specific examples”, or “in some examples” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.
Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments can not be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims (19)

What is claimed is:
1. A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof,
Figure US09598401-20170321-C00083
wherein
X is O, S or NH;
Y1 is CH or N;
Y2 is CR2 or N;
Y3 is CR3 or N;
Y4 is CR4 or N;
E is N or CH;
Figure US09598401-20170321-P00002
is either a single bond or a double bond, provided that: (1) when
Figure US09598401-20170321-P00003
is a single bond, G is CH or N; or (2) when
Figure US09598401-20170321-P00004
is a double bond, G is C;
Ar is
Figure US09598401-20170321-C00084
wherein each W is independently O or NH;
each Rx is independently D, F, Cl, C1-C6 alkyl, C1-C6 haloalkyl, —NR11R11a, —OR10, —(C1-C6 alkylene)-NR11R11a, —(C1-C6 alkylene)-OR10, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a or —(C1-C6 alkylene)-aryl, or two Rx on two adjacent ring carbon atoms, together with the ring carbon atoms to which they are attached, form a C3-C6 carbocyclic or 3-6 membered heterocyclic ring;
k is 0, 1, 2, 3 or 4;
each of R1, R2, R3 and R4 is independently H, D, F, Cl, Br, I, NO2, CN, —SCN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R5, R6 and R7 is independently H, D, F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, -alkylene-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R8 is independently H, D, alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl, wherein each of alkenyl, alkynyl, alkoxy and cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R9 is independently F, Cl, Br, I, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R10 is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl and heteroarylalkylene is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino;
each R11 and R11a is independently H, D, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl or heteroarylalkylene, or R11 and R11a, together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein each of alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl, heterocyclylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene and heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, alkyl, alkoxy, alkylthio and alkylamino; and
m is 3, 4, 5 or 6.
2. The compound according to claim 1 having Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof,
Figure US09598401-20170321-C00085
3. The compound according to claim 1, wherein each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R1)C(═O)R10, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; or
wherein each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl or (C1-C5 heteroaryl)-(C1-C4 alkylene)-, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl and (C1-C5 heteroaryl)-(C1-C4 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
4. The compound according to claim 1, wherein each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C6 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; or
wherein each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
5. The compound according to claim 1, wherein each R10 is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; and
each R11 and R11a is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C10 heterocyclic ring, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl and C2-C10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
6. The compound according to claim 1 having Formula (III):
Figure US09598401-20170321-C00086
wherein
each Rx is independently D, Cl, Me, —CF3, —OMe, OH or NH2;
k is 0, 1, 2, 3 or 4;
R1 is H, D, F, Cl, CN, —OR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl or C1-C5 heteroaryl, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocyclyl, phenyl and C1-C5 heteroaryl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino;
each R10 is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl;
each R11 and R11a is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl or C3-C8 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C7 heterocyclic ring; and
m is 3, 4, 5 or 6.
7. The compound according to claim 6 having Formula (IV):
Figure US09598401-20170321-C00087
8. The compound according to claim 6, wherein R1 is H, D, F, Cl, CN, OH, NH2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2.
9. The compound according to claim 6, wherein each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)NH2, —CH2—C(═O)NH2, —C(═O)NMe2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2, with the proviso that at least one of R5, R6 and R7 is not H.
10. A compound having one of the following structures:
Figure US09598401-20170321-C00088
Figure US09598401-20170321-C00089
Figure US09598401-20170321-C00090
Figure US09598401-20170321-C00091
Figure US09598401-20170321-C00092
Figure US09598401-20170321-C00093
Figure US09598401-20170321-C00094
Figure US09598401-20170321-C00095
Figure US09598401-20170321-C00096
Figure US09598401-20170321-C00097
Figure US09598401-20170321-C00098
Figure US09598401-20170321-C00099
or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising the compound according to claim 1, and a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof.
12. The pharmaceutical composition according to claim 11, further comprising at least one therapeutic agent for central nervous system dysfunction, wherein the therapeutic agent for central nervous system dysfunction is an antidepressant, an antianxiety agent, a lithium agent of a mood stabilizer, an atypical antipsychotic agent, an antiepileptic agent, an anti-Parkinson agent, a selective serotonin reuptake inhibitor, a 5-HT1A receptor agonist, a central nervous system stimulant, a nicotine antagonist or a combination thereof; or
wherein the therapeutic agent for central nervous system dysfunction is amitriptyline, desipramine, mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine, vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, vestipitant, chlordiazepoxide, perphenazine or a combination thereof.
13. A method of treating or lessening the severity of a central nervous system dysfunction in a human comprising administrating a therapeutically effective amount of the compound according to claim 1 to the human, wherein the central nervous system dysfunction is depression, anxiety, mania, schizophrenia, bipolar disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, Parkinson's disease, and Huntington's disease.
14. A method of treating or lessening the severity of a central nervous system dysfunction in a human comprising administrating a therapeutically effective amount of the pharmaceutical composition according to claim 11 to the human, wherein the central nervous system dysfunction is depression, anxiety, mania, schizophrenia, bipolar disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, Parkinson's disease, and Huntington's disease.
15. The compound according to claim 2, wherein each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —OC(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)C(═O)R10, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; or
wherein each of R1, R2, R3 and R4 is independently H, D, F, Cl, NO2, CN, —OR10, —SR10, —NR11R11a, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl or (C1-C5 heteroaryl)-(C1-C4 alkylene)-, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl)-(C1-C4 alkylene)-, C2-C7 heterocyclyl, (C2-C7 heterocyclyl)-(C1-C4 alkylene)-, phenyl, (phenyl)-(C1-C4 alkylene)-, C1-C5 heteroaryl and (C1-C5 heteroaryl)-(C1-C4 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
16. The compound according to claim 2, wherein each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C6 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl or (C1-C9 heteroaryl)-(C1-C6 alkylene)-, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C10 cycloalkyl, (C3-C10 cycloalkyl)-(C1-C6 alkylene)-, C2-C10 heterocyclyl, (C2-C10 heterocyclyl)-(C1-C6 alkylene)-, C6-C10 aryl, (C6-C10 aryl)-(C1-C6 alkylene)-, C1-C9 heteroaryl and (C1-C9 heteroaryl)-(C1-C6 alkylene)- is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; or
wherein each R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)R10, —C(═O)OR10, —C(═O)NR11R11a, —(C1-C4 alkylene)-C(═O)NR11R11a, —OC(═O)R10, —N(R11)C(═O)R10, —S(═O)R10, —S(═O)2R10, —S(═O)2OR10, —S(═O)2NR11R11a, —N(R11)S(═O)2R10, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkylamino, with the proviso that at least one of R5, R6 and R7 is not H, wherein each of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylamino.
17. The compound according to claim 2, wherein each R10 is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl and C3-C10 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino; and
each R11 and R11a is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl or C3-C10 cycloalkyl, or R11 and R11a, together with the nitrogen atom to which they are attached, form a C2-C10 heterocyclic ring, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl and C2-C10 heterocyclic ring is optionally substituted with one or more substituents independently selected from D, F, Cl, N3, CN, OH, SH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylamino.
18. The compound according to claim 7, wherein R1 is H, D, F, Cl, CN, OH, NH2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2.
19. The compound according to claim 7, wherein each of R5, R6 and R7 is independently H, D, F, Cl, NO2, CN, NH2, —C(═O)H, —C(═O)OH, —C(═O)OMe, —C(═O)NH2, —CH2—C(═O)NH2, —C(═O)NMe2, Me, Et, n-Pr, i-Pr, —CF3, —OMe, —OEt, —O(i-Pr), —O(t-Bu) or —NMe2, with the proviso that at least one of R5, R6 and R7 is not H.
US14/787,774 2013-07-29 2014-07-28 Substituted heteroaryl compounds and methods of use thereof Active US9598401B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201310322334 2013-07-29
CN201310322334.6 2013-07-29
CN201310322334 2013-07-29
PCT/CN2014/083135 WO2015014256A1 (en) 2013-07-29 2014-07-28 Substituted heteroaryl compounds and methods of use thereof

Publications (2)

Publication Number Publication Date
US20160083370A1 US20160083370A1 (en) 2016-03-24
US9598401B2 true US9598401B2 (en) 2017-03-21

Family

ID=52430994

Family Applications (1)

Application Number Title Priority Date Filing Date
US14/787,774 Active US9598401B2 (en) 2013-07-29 2014-07-28 Substituted heteroaryl compounds and methods of use thereof

Country Status (4)

Country Link
US (1) US9598401B2 (en)
EP (1) EP3027607B1 (en)
CN (1) CN104337812B (en)
WO (1) WO2015014256A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106065018B (en) * 2015-04-23 2020-04-21 广东东阳光药业有限公司 Substituted indole compounds, methods of use and uses thereof

Citations (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3188313A (en) 1959-09-25 1965-06-08 Sterling Drug Inc 1-[(1-, 2- and 3-indolyl)-lower]piperazine derivatives and intermediates and processes for the preparation thereof
US4954502A (en) 1988-06-10 1990-09-04 Bristol-Myers Squibb Company 1-indolyalkyl-4-(substituted-pyridinyl)piperazines
US4954503A (en) 1989-09-11 1990-09-04 Hoechst-Roussel Pharmaceuticals, Inc. 3-(1-substituted-4-piperazinyl)-1H-indazoles
US5002948A (en) 1988-12-28 1991-03-26 H. Lundbeck A/S 3-[4-[4-substituted-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindoles
US5010079A (en) 1988-08-03 1991-04-23 Synthelabo Indolone derivatives, their preparation and their application in therapy
US5077293A (en) 1990-06-29 1991-12-31 Bristol-Myers Squibb Co. 1-indolyalkyl-4-(alkoxypyrimidinyl)piperazines
US5106850A (en) 1989-07-13 1992-04-21 Merck Patent Gesellschaft Mit Beschrankter Haftung Indole derivatives
US5242925A (en) 1991-08-22 1993-09-07 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperazinylbenzodioxane derivatives
US5270312A (en) 1990-11-05 1993-12-14 Warner-Lambert Company Substituted piperazines as central nervous system agents
JPH0641071A (en) 1991-09-06 1994-02-15 Taisho Pharmaceut Co Ltd Indoleacetic ester derivative
US5300506A (en) 1990-06-29 1994-04-05 Bristol-Myers Squibb Company Indolylalkyl derivatives of pyrimidinylpiperazine for treating vascular headache
US5418237A (en) 1991-01-22 1995-05-23 Merck Patent Gesellschaft Mit Beschrankter Haftung Indole derivatives
US5434154A (en) 1991-12-19 1995-07-18 Bristol-Myers Squibb Company Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkylpiperazines
WO1995035293A1 (en) 1994-06-21 1995-12-28 Vita-Invest, S.A. Indol derivatives useful for the treatment of migraine, composition and utilization
US5521188A (en) 1993-09-16 1996-05-28 Bristol-Myers Squibb Company Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines
US5532241A (en) 1993-09-30 1996-07-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperidines and piperazines
US5550239A (en) 1994-11-08 1996-08-27 Bristol-Myers Squibb Company Process for large-scale production of indolyl alkyl pyrimidinyl piperazine compounds
US5614524A (en) 1994-05-19 1997-03-25 Merck Sharp & Dohme Ltd. Piperazine derivatives as 5-HT1 Agonists
US5618816A (en) 1995-03-02 1997-04-08 Bristol-Myers Squibb Company Antimigraine 1,2,5-thiadiazole derivatives of indolylalkyl-pyridnyl and pyrimidinylpiperazines
US5681954A (en) 1993-05-14 1997-10-28 Daiichi Pharmaceutical Co., Ltd. Piperazine derivatives
US5763444A (en) 1995-08-14 1998-06-09 Bristol-Myers Squibb Company Antidepressant 1-arylalkyl-4-(alkoxy pyridinyl)-and 4-(alkoxypyrimidinyl) piperazine derivatives
CN1184478A (en) 1995-03-22 1998-06-10 大正制药株式会社 Thiazole derivatives
WO1999067237A1 (en) 1998-06-19 1999-12-29 H. Lundbeck A/S 4,5,6 and 7-indole and indoline derivatives, their preparation and use
EP1078928A1 (en) 1999-08-27 2001-02-28 Adir Et Compagnie Pyridine derivatives, process for their preparation and pharmaceutical compositions containing them
WO2001014330A2 (en) 1999-08-23 2001-03-01 Solvay Pharmaceuticals B.V. Phenylpiperazines as serotonin reuptake inhibitors
US6251908B1 (en) 1997-07-18 2001-06-26 Merck Patent Gesellschaft Mit Beschraenkter Haftung Piperazine derivatives
WO2001049679A1 (en) 1999-12-30 2001-07-12 H. Lundbeck A/S 4-phenyl-1-piperazinyl, -piperidinyl and -tetrahydropyridyl derivatives
US6310068B1 (en) 1995-04-05 2001-10-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzonitriles and benzofluorides
JP2002053553A (en) 1993-05-14 2002-02-19 Dai Ichi Seiyaku Co Ltd Piperidine derivative
WO2002044170A2 (en) 2000-11-29 2002-06-06 Laboratorios Vita, S.A. Benzothiophene derivative compounds, process of preparation and use thereof
US6476035B1 (en) 1997-07-25 2002-11-05 Lundbeck & Co As H Indole and 2,3-dihydroindole derivatives, their preparation and use
US6486153B1 (en) 1997-09-04 2002-11-26 Merck Sharp & Dohme Ltd. Phenylindole derivatives as 5-HT2A receptor ligands
US6518273B1 (en) 1999-03-04 2003-02-11 Merck Sharp & Dohme Ltd. 2-aryl indole derivative as antagonists of tachykinins
US6596722B2 (en) 1999-01-22 2003-07-22 H. Lundbeck A/S Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use
WO2003070723A1 (en) 2002-02-22 2003-08-28 H. Lundbeck A/S 5-heteroaryl substituted indoles
WO2003076400A1 (en) 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. New inhibitors of histone deacetylase
WO2003101994A1 (en) 2002-05-29 2003-12-11 Abbott Laboratories Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction
WO2004041815A1 (en) 2002-11-08 2004-05-21 Merck Patent Gmbh Indole derivative with 5ht1a affinity
US20060122191A1 (en) 2002-12-17 2006-06-08 Timo Heinrich N-(indolethyl-)cycloamine compounds
US20060122175A1 (en) 2004-12-07 2006-06-08 Solvay Pharmaceuticals B.V. Benzdioxane piperazine derivatives with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites
WO2006061379A1 (en) 2004-12-08 2006-06-15 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition
WO2006061374A1 (en) 2004-12-07 2006-06-15 Solvay Pharmaceuticals B.V. Benzdioxane piperazine derivatives with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites
US20060160824A1 (en) 2003-06-16 2006-07-20 Timo Heinrich Indole derivatives as serotonin reuptake inhibitors
US7244846B2 (en) 2001-03-14 2007-07-17 Merck Patent Gmbh Substituted benzofuran-2-carboxamides derivatives
US7276603B2 (en) 2003-05-02 2007-10-02 Wyeth Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use
US7332495B2 (en) 2002-05-22 2008-02-19 Nhwa Pharma. Corporation Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent
US20090054454A1 (en) 2007-08-21 2009-02-26 Aranapakam Mudumbai Venkatesan Benzofuranyl- and benzothienyl- piperazinyl quinolines and methods of their use
US7576086B2 (en) 2002-06-03 2009-08-18 Shanghai Institute Of Pharmaceutical Industry Aralkyl-alcohol peiperazine derivatives and their uses as antidepressant
US20090238761A1 (en) 2005-01-03 2009-09-24 Universita Degli Studi Di Siena Novel Aryl Piperazine Derivatives With Medical Utility
US7829565B2 (en) 2003-06-16 2010-11-09 Merck Patent Gmbh Indole derivatives as serotonin reuptake inhibitors
US20110059982A1 (en) 2008-03-14 2011-03-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Azaindole compounds for treatment of central nervous system disorders
US7968551B2 (en) 2003-04-04 2011-06-28 Merck Patent Gmbh Chromenoneindoles
CN102372703A (en) 2010-08-18 2012-03-14 复旦大学 Indole benzothiazole derivative and pharmaceutical use thereof
WO2012170209A2 (en) 2011-05-23 2012-12-13 Nectid, Inc. Benzofuran-2 carboxamide compounds
US20130064770A1 (en) 2010-05-28 2013-03-14 Ge Healthcare Limited Radiolabeled compounds and methods thereof
CN102993186A (en) 2012-12-20 2013-03-27 北京海步国际医药科技发展有限公司 Novel piperazine derivative
US8680097B2 (en) 2008-07-02 2014-03-25 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. Benzothiophene alkanol piperazine derivatives and their use as antidepressant
CN104163813A (en) 2013-05-16 2014-11-26 广东东阳光药业有限公司 Substituted indole compound, and preparation method and use thereof

Patent Citations (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3188313A (en) 1959-09-25 1965-06-08 Sterling Drug Inc 1-[(1-, 2- and 3-indolyl)-lower]piperazine derivatives and intermediates and processes for the preparation thereof
US4954502A (en) 1988-06-10 1990-09-04 Bristol-Myers Squibb Company 1-indolyalkyl-4-(substituted-pyridinyl)piperazines
US5010079A (en) 1988-08-03 1991-04-23 Synthelabo Indolone derivatives, their preparation and their application in therapy
US5002948A (en) 1988-12-28 1991-03-26 H. Lundbeck A/S 3-[4-[4-substituted-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindoles
US5106850A (en) 1989-07-13 1992-04-21 Merck Patent Gesellschaft Mit Beschrankter Haftung Indole derivatives
US4954503A (en) 1989-09-11 1990-09-04 Hoechst-Roussel Pharmaceuticals, Inc. 3-(1-substituted-4-piperazinyl)-1H-indazoles
US5300506A (en) 1990-06-29 1994-04-05 Bristol-Myers Squibb Company Indolylalkyl derivatives of pyrimidinylpiperazine for treating vascular headache
US5077293A (en) 1990-06-29 1991-12-31 Bristol-Myers Squibb Co. 1-indolyalkyl-4-(alkoxypyrimidinyl)piperazines
US5270312A (en) 1990-11-05 1993-12-14 Warner-Lambert Company Substituted piperazines as central nervous system agents
US5418237A (en) 1991-01-22 1995-05-23 Merck Patent Gesellschaft Mit Beschrankter Haftung Indole derivatives
US5242925A (en) 1991-08-22 1993-09-07 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperazinylbenzodioxane derivatives
JPH0641071A (en) 1991-09-06 1994-02-15 Taisho Pharmaceut Co Ltd Indoleacetic ester derivative
US5434154A (en) 1991-12-19 1995-07-18 Bristol-Myers Squibb Company Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkylpiperazines
US5681954A (en) 1993-05-14 1997-10-28 Daiichi Pharmaceutical Co., Ltd. Piperazine derivatives
JP2002053553A (en) 1993-05-14 2002-02-19 Dai Ichi Seiyaku Co Ltd Piperidine derivative
US5521188A (en) 1993-09-16 1996-05-28 Bristol-Myers Squibb Company Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines
US5532241A (en) 1993-09-30 1996-07-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperidines and piperazines
US5614524A (en) 1994-05-19 1997-03-25 Merck Sharp & Dohme Ltd. Piperazine derivatives as 5-HT1 Agonists
WO1995035293A1 (en) 1994-06-21 1995-12-28 Vita-Invest, S.A. Indol derivatives useful for the treatment of migraine, composition and utilization
US5550239A (en) 1994-11-08 1996-08-27 Bristol-Myers Squibb Company Process for large-scale production of indolyl alkyl pyrimidinyl piperazine compounds
US5618816A (en) 1995-03-02 1997-04-08 Bristol-Myers Squibb Company Antimigraine 1,2,5-thiadiazole derivatives of indolylalkyl-pyridnyl and pyrimidinylpiperazines
CN1184478A (en) 1995-03-22 1998-06-10 大正制药株式会社 Thiazole derivatives
US6310068B1 (en) 1995-04-05 2001-10-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzonitriles and benzofluorides
US5763444A (en) 1995-08-14 1998-06-09 Bristol-Myers Squibb Company Antidepressant 1-arylalkyl-4-(alkoxy pyridinyl)-and 4-(alkoxypyrimidinyl) piperazine derivatives
US6251908B1 (en) 1997-07-18 2001-06-26 Merck Patent Gesellschaft Mit Beschraenkter Haftung Piperazine derivatives
US6476035B1 (en) 1997-07-25 2002-11-05 Lundbeck & Co As H Indole and 2,3-dihydroindole derivatives, their preparation and use
US6486153B1 (en) 1997-09-04 2002-11-26 Merck Sharp & Dohme Ltd. Phenylindole derivatives as 5-HT2A receptor ligands
WO1999067237A1 (en) 1998-06-19 1999-12-29 H. Lundbeck A/S 4,5,6 and 7-indole and indoline derivatives, their preparation and use
US6596722B2 (en) 1999-01-22 2003-07-22 H. Lundbeck A/S Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use
US6518273B1 (en) 1999-03-04 2003-02-11 Merck Sharp & Dohme Ltd. 2-aryl indole derivative as antagonists of tachykinins
WO2001014330A2 (en) 1999-08-23 2001-03-01 Solvay Pharmaceuticals B.V. Phenylpiperazines as serotonin reuptake inhibitors
EP1078928A1 (en) 1999-08-27 2001-02-28 Adir Et Compagnie Pyridine derivatives, process for their preparation and pharmaceutical compositions containing them
WO2001049679A1 (en) 1999-12-30 2001-07-12 H. Lundbeck A/S 4-phenyl-1-piperazinyl, -piperidinyl and -tetrahydropyridyl derivatives
WO2002044170A2 (en) 2000-11-29 2002-06-06 Laboratorios Vita, S.A. Benzothiophene derivative compounds, process of preparation and use thereof
US7244846B2 (en) 2001-03-14 2007-07-17 Merck Patent Gmbh Substituted benzofuran-2-carboxamides derivatives
WO2003070723A1 (en) 2002-02-22 2003-08-28 H. Lundbeck A/S 5-heteroaryl substituted indoles
WO2003076400A1 (en) 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. New inhibitors of histone deacetylase
US7332495B2 (en) 2002-05-22 2008-02-19 Nhwa Pharma. Corporation Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent
WO2003101994A1 (en) 2002-05-29 2003-12-11 Abbott Laboratories Fused bicyclic aromatic compounds that are useful in treating sexual dysfunction
US7576086B2 (en) 2002-06-03 2009-08-18 Shanghai Institute Of Pharmaceutical Industry Aralkyl-alcohol peiperazine derivatives and their uses as antidepressant
WO2004041815A1 (en) 2002-11-08 2004-05-21 Merck Patent Gmbh Indole derivative with 5ht1a affinity
US20060122191A1 (en) 2002-12-17 2006-06-08 Timo Heinrich N-(indolethyl-)cycloamine compounds
US7968551B2 (en) 2003-04-04 2011-06-28 Merck Patent Gmbh Chromenoneindoles
US7276603B2 (en) 2003-05-02 2007-10-02 Wyeth Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use
US7829565B2 (en) 2003-06-16 2010-11-09 Merck Patent Gmbh Indole derivatives as serotonin reuptake inhibitors
US20060160824A1 (en) 2003-06-16 2006-07-20 Timo Heinrich Indole derivatives as serotonin reuptake inhibitors
US20060122175A1 (en) 2004-12-07 2006-06-08 Solvay Pharmaceuticals B.V. Benzdioxane piperazine derivatives with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites
WO2006061374A1 (en) 2004-12-07 2006-06-15 Solvay Pharmaceuticals B.V. Benzdioxane piperazine derivatives with a combination of affinity for dopamine-d2 receptors and serotonin reuptake sites
WO2006061377A1 (en) 2004-12-08 2006-06-15 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition
WO2006061379A1 (en) 2004-12-08 2006-06-15 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition
US20090238761A1 (en) 2005-01-03 2009-09-24 Universita Degli Studi Di Siena Novel Aryl Piperazine Derivatives With Medical Utility
US20090054454A1 (en) 2007-08-21 2009-02-26 Aranapakam Mudumbai Venkatesan Benzofuranyl- and benzothienyl- piperazinyl quinolines and methods of their use
US20110059982A1 (en) 2008-03-14 2011-03-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Azaindole compounds for treatment of central nervous system disorders
US8680097B2 (en) 2008-07-02 2014-03-25 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. Benzothiophene alkanol piperazine derivatives and their use as antidepressant
US20130064770A1 (en) 2010-05-28 2013-03-14 Ge Healthcare Limited Radiolabeled compounds and methods thereof
CN102372703A (en) 2010-08-18 2012-03-14 复旦大学 Indole benzothiazole derivative and pharmaceutical use thereof
WO2012170209A2 (en) 2011-05-23 2012-12-13 Nectid, Inc. Benzofuran-2 carboxamide compounds
CN102993186A (en) 2012-12-20 2013-03-27 北京海步国际医药科技发展有限公司 Novel piperazine derivative
CN104163813A (en) 2013-05-16 2014-11-26 广东东阳光药业有限公司 Substituted indole compound, and preparation method and use thereof

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
B Testa et al., Prodrug Design in, 5 Encyclopedia of Pharmaceutical Technology, 3008-3014 (J. Swarbrick ed., 3rd ed., 2007). *
G.J. Yohrling et al., 82 Journal of Neurochemistry, 1416-1423 (2002). *
H. Girouard et al., 100 Journal of Applied Physiology, 328-335, 332 (2006). *
Heinrich et al., Indolebutylamines as Selective 5-HT1A Agonists, Journal of Medicinal Chemistry, 2004, 47(19): 4677-4683.
International Search Report of PCT/CN2014/083135.
J.D. Mitchell et al., 369 The Lancet, 2031-2041 (2007). *
J.T. O'Brien et al., 2 The Lancet Neurology, 89-98, 96 (2003). *
Llado-Pelfort et al., 22 Cerebral Cortex, 1487-1487 (2012). *
Newman-Tancredi et al., 216 Psychopharmacology, 451-473 (2011). *
Ono, 17 CNS Neuroscience & Therapeutics, 59-65 (2010). *
P. Celada et al., 27 CNS Drugs, 703-716 (2013). *
P.A. LeWitt, 359 New England Journal of Medicine, 2468-2473 (2008). *
Pessoa-Mahana et al., Synthesis, 5-hydroxytryptamine1A receptor affinity and docking studies of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives, Chemical and Pharmaceutical Bulletin, 2012, 60(5): 632-638.
R. S. Shah et al., 52 Biomedicine & Pharmacotherapy, 199-207 (2008). *
S. Judge et al., 111 Pharmacology & Therapeutics, 224-259 (2006). *
V. Brinkmann et al., 9 Nature Reviews | Drug Discovery, 883-897 (2010). *
Written Opinion of PCT/CN2014/083135.
Y. Agid et al., 6 Nature Reviews | Drug Discovery 189-201, 189 (2007). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof

Also Published As

Publication number Publication date
EP3027607A1 (en) 2016-06-08
EP3027607B1 (en) 2020-08-26
CN104337812B (en) 2018-09-14
CN104337812A (en) 2015-02-11
EP3027607A4 (en) 2017-02-22
WO2015014256A1 (en) 2015-02-05
US20160083370A1 (en) 2016-03-24

Similar Documents

Publication Publication Date Title
US9714232B2 (en) Substituted piperazine compounds and methods of use thereof
CN109574993B (en) Substituted pyrimidinylpiperazine compounds and uses thereof
US20080021026A1 (en) Benzothiophene inhibitors of rho kinase
US10316025B2 (en) Substituted piperazine compounds and methods of use and use thereof
US11390623B2 (en) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligands
CA3107145A1 (en) Pyridinylmethylenepiperidine derivatives and uses thereof
WO2015169180A1 (en) Substituted piperazine compounds and methods and use thereof
US9974785B2 (en) Aromatic heterocyclic derivatives and pharmaceutical applications thereof
US20230257381A1 (en) 7-(piperidin-1-yl)-4h-pyrimido[1,2-b]pyridazin-4-one derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor m4
US9598401B2 (en) Substituted heteroaryl compounds and methods of use thereof
CN111187251B (en) Pyridinoylpiperidine derivatives and their use
CN111187252B (en) Pyridinoyl azaspiroheptane derivatives and their use
US10196383B2 (en) Substituted quinazoline compounds and preparation and uses thereof
CN110845402B (en) Pyridine methylene piperazine derivatives and uses thereof
CN106065018B (en) Substituted indole compounds, methods of use and uses thereof
CN106045967B (en) Substituted heterocyclic compounds and their use in medicine
CN106795160B (en) Substituted benzazolyl compounds and its application method and purposes
CN106045966B (en) Substituted heterocyclic compounds and their use in medicine

Legal Events

Date Code Title Description
AS Assignment

Owner name: SUNSHINE LAKE PHARMA CO., LTD., CHINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ZHANG, YINGJUN;JIN, CHUANFEI;ZHOU, RONGQI;REEL/FRAME:036941/0639

Effective date: 20130914

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SUNSHINE LAKE PHARMA CO., LTD.;REEL/FRAME:050781/0929

Effective date: 20190906

AS Assignment

Owner name: SUNSHINE LAKE PHARMA CO., LTD., CHINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED;REEL/FRAME:052921/0778

Effective date: 20200525

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8